key: cord-0855489-35h19t4h
authors: Shen, Qingtang; Wang, Yifan E.; Palazzo, Alexander F.
title: Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection
date: 2021-06-29
journal: J Biol Chem
DOI: 10.1016/j.jbc.2021.100856
sha: 367920fa2e821654d0a10d78dd45695e3a0c0f54
doc_id: 855489
cord_uid: 35h19t4h

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of 110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.

A defining feature of all eukaryotic cells is the nuclear envelope, which encloses the cell's genetic material and separates the nucleoplasm, where RNA is synthesized and processed, from the cytoplasm, where mRNA is translated into proteins (1) (2) (3) . The nuclear envelope is contiguous with the endoplasmic reticulum (ER), and it contains two membranes, the outer and inner nuclear membranes, which are separated by a luminal space that is contiguous with the lumen of the ER. Within the nuclear envelope, thousands of macromolecular channels are embedded, termed the nuclear pore complexes (4) (5) (6) , which mediate the nucleocytoplasmic trafficking of macromolecules needed for a number of cellular processes, such as DNA replication, transcription, translation, and antiviral innate immunity (7) . Mutations and gene fusions of nucleoporins (Nups) cause many diverse human diseases including autoimmune diseases (RanBP2/Nup358) and increased susceptibility to viral infections (translocated promoter region [TPR] , Nup153, and RanBP2/Nup358) (8, 9) . Despite this, the exact molecular mechanisms by which these mutations contribute to these various pathologies remain mysterious. In this review, we discuss recent advances that reveal how nuclear pore proteins contribute to antiviral innate immunity and highlight how viruses manipulate this cellular machinery to evade the innate immune response and favor viral infection. Finally, we briefly review recent progress that has been made in developing novel antiviral therapeutics that target nucleocytoplasmic transport.

The nuclear pore complex is one of the largest protein complexes in the cell, with an estimated molecular mass of 50 MDa in yeast and 110 to 125 MDa in metazoans and an outer diameter of 80 to 120 nm and an inner diameter of 40 nm (10, 11) . Each nuclear pore complex is composed of multiple copies (ranging from 8 to 64) of about 34 different nuclear pore proteins, known as Nups (labeled Nup followed by their predicted molecular weight), most of which are conserved among different organisms (8, (12) (13) (14) (15) (16) . Structurally, the nuclear pore complex consists of an inner ring, which resides in the center of the pore, cytoplasmic, and nuclear rings, which are similar to each other and attach to either side of the inner ring, cytoplasmic filaments, which project from the cytoplasmic ring, and a nuclear basket, which is attached to the nuclear ring (8, (15) (16) (17) (18) (19) (Fig. 1A) . Surrounding each nuclear pore complex is a highly curved section of the nuclear envelope where the outer nuclear membrane is fused with the inner nuclear membrane (19) . Across this membrane, and within the lumen of the nuclear envelope, a circular scaffold known as the luminal ring surrounds the nuclear pore complex (20) (21) (22) .

The central channel of the pore is lined with Nups that contain phenylalanine-glycine repeats (FG-Nups). These repeats interact with one another to form a meshwork, which appears to phase separate from the bulk solution and thus acts as a permeability barrier (23) . The meshwork prevents the movement of macromolecules and complexes that are larger than 30 to 40 kDa (e.g., proteins, RNAs, and viruses). To cross the pore, these macromolecules need to be ferried by nuclear transport receptors (also known as importins, exportins, transportins, or karyopherins) (24) (25) (26) (27) .

In general, the formation and disassembly of nuclear transport receptors with their macromolecular cargos are regulated by the small Ras-like GTPase Ran, which cycles between GDP-bound and GTP-bound states. The conversion from GDP-to GTP-bound state is promoted by the guanine nuclear exchange factor regulator of chromosome condensation 1, which resides in the nucleus, whereas the hydrolysis of Figure 1 . Schematic representation of the nuclear pore complex and the nuclear import and export cycles. A, the nuclear pore complex is embedded into the nuclear envelope and composed of nucleoporins (Nups) that are structurally arranged into the inner ring, cytoplasmic and nuclear rings, cytoplasmic filaments, and nuclear basket. Within the lumen of the nuclear envelope, a circular scaffold known as the luminal ring surrounds the nuclear pore complex. The central channel of the pore is lined with Nups that contain phenylalanine-glycine repeats (FG-Nups). B, the movement of macromolecules and complexes across the nuclear envelope is facilitated by nuclear transport receptors. In the canonical nuclear import pathway, a cargo is recognized by nuclear import receptors importin-α (imp-α) and importin-β (imp-β) and is ferried across the pore. Once in the nucleus, the binding of Ran-GTP to importinβ causes the disassembly of the import complex and releases the cargo. Importin-β bound to Ran-GTP is transported back to the cytoplasm, whereas importin-α is recycled by CAS protein (also known as exportin2). GTP hydrolysis of Ran releases importin-β for the next round of import. For nuclear export, a cargo with nuclear export signal is usually bound by CRM1 (also known as exportin1). After the export complex enters the cytoplasm, Ran-GTP is hydrolyzed to Ran-GDP, and this promotes dissociation of the complex. The export of mRNAs is different from that of proteins because mRNAs are bound by many proteins in the form of messenger ribonucleoprotein (mRNP) complexes. mRNA export requires the nuclear transport receptor NXF1/NXT1 (also known as TAP/p15). Following the completion of export, the mRNP undergoes remodeling events where the transport receptors and many bound proteins are removed, whereas other protein factors such as ribosomes join. CAS, cellular apoptosis susceptibility; CRM1, chromosomal maintenance 1; imp-α, importin-α; imp-β, importin-β; mRNP, messenger ribonucleoprotein; NXF1, nuclear RNA export factor 1; NXT1, nuclear transport factor 2-like export factor 1.

GTP to GDP is catalyzed by Ran's intrinsic GTPase activity that is stimulated by Ran GTPase-activating protein 1, which is tightly associated with the cytoplasmic filament protein RanBP2/Nup358. As a result of these two locally restricted reactions, the ratio of Ran-GTP/Ran-GDP is 200-fold higher in the nucleus than in the cytoplasm (28, 29) . In addition to this "Ran-GTP gradient," overall Ran concentration is kept relatively high in the nucleus and low in the cytoplasm because of the activity of nuclear transport factor 2 (NTF2), which associates with Ran-GDP in the cytosol, then ferries it into the nucleus where upon GTP hydrolysis releases Ran (30-36). As such, the nucleoplasm acts as a sink for Ran, and this is catalyzed by the energy released by the GTP hydrolysis reaction.

GTP hydrolysis drives all Ran-dependent import and export. Proteins that are imported contain nuclear localization signals (often referred to as NLSs), which are recognized by specialized sets of import receptors in the cytoplasm. Importin-α (also known as karyopherin-α) binds to canonical NLSs, which consist of one or more clusters of basic amino acids (37-40). Simultaneously, importin-α binds to importin-β (also known as karyopherin-β) (41, 42), which interacts with FG repeats and can ferry associated proteins across the nuclear pore (43, 44). Once inside the nucleus, Ran-GTP binds to importin-β and causes the disassembly of the cargo-importin-α/β complex (43, 45). As such, the nucleoplasm becomes a sink for nuclear import substrate proteins. The importin-β-Ran-GTP complex can then diffuse back to the cytoplasm, whereas importin-α is recycled back by cellular apoptosis susceptibility protein (also known as exportin2) (46). Subsequent GTP hydrolysis, stimulated by Ran GTPase-activating protein 1, releases importinβ for the next round of import (Fig. 1B) . In some cases, proteins may contain noncanonical NLSs. For proteins that contain proline-tyrosine NLSs, such as heterogenous nuclear ribonucleoproteins (hnRNPs), they are imported by transportin-1 (also known as importin-β2) (47-49). Proteins can also be directly recognized by importin-β, and examples of these are ribosomal proteins, the HIV proteins Rev and Tat (40, (50) (51) (52) .

For the nuclear export of protein substrates, these typically contain nuclear export signals (often referred to as NESs), which are usually leucine-rich sequences and recognized by the major exportin, chromosomal maintenance 1 (CRM1, also known as exportin1/XPO1) bound to Ran-GTP (53, 54) . CRM1 interacts with FG repeats and thus ferries its cargoes across the pore. After this complex enters the cytoplasm, GTP hydrolysis of Ran promotes the dissociation of the export complex and the release of cargo (Fig. 1B) . As such, the cytosol acts as a sink for these protein cargoes. Cargo-free CRM1 is then free to diffuse back across the pore into the nucleoplasm. For the export of most noncoding RNAs and some proteins, CRM1 does not bind to these cargos directly but is instead recruited to the RNAs by adapter proteins such as PHAX (phosphorylated adapter RNA export protein) (55) (56) (57) (58) (59) .

The export of mRNAs is different from that of proteins and most noncoding RNAs because mRNAs are associated with a dynamic repertoire of proteins in the form of large messenger ribonucleoprotein (mRNP) complexes (60, 61) . Most mRNAs do not rely on CRM1 and Ran for export but instead require the nuclear transport receptor heterodimer nuclear RNA export factor 1 (NXF1)/NTF2-like export factor 1 (NXT1), which is structurally related to NTF2 (62) (63) (64) . NXF1/NXT1 (also known as TAP/p15) is recruited to the mRNP by the transcription export (TREX) complex and serine and arginine-rich proteins. TREX is typically recruited to the mRNA during transcription and RNA processing, whereas serine and arginine-rich proteins bind to particular motifs in the mRNA (61, 65, 66) . As is the case with NTF2, NXF1/NXT1 directly binds to FG-Nups and thus facilitates movement across the pore. Following the completion of translocation, the DEAD-box protein Dbp5 and mRNA export factor RAE1/Gle1, which are associated with the cytoplasmic filaments of the nuclear pore, are thought to remove the transport receptors from the mRNP in an ATP-dependent manner and prevent the mRNA from returning to the nucleus (67-69) (Fig. 1B) . This exchange of mRNA-associated proteins during export is commonly referred to as mRNP remodeling, and this likely plays key roles in regulating mRNA export and mRNA translation (70, 71) .

Other critical complexes are TREX2 (72) (73) (74) (75) (76) , whose components bind to the nuclear basket components TPR and Nup153 (77, 78) , and are required for efficient nuclear mRNA export (79) (80) (81) ; however, the exact details of how these function remain unclear although they likely play roles in mRNP remodeling.

The interaction of the innate immune response with nuclear pore proteins and nuclear transport receptors The innate immune system is the first line of host defense and evolutionarily conserved across vertebrates. It utilizes a limited number of pattern-recognition receptors (PRRs) to detect and defend against microbial pathogens. PRRs recognize various conserved molecular structures termed pathogenassociated molecular patterns (PAMPs) (82) . As DNA and RNA either carry genetic information or act as replication intermediates for all microbial pathogens, they serve as PAMPs and are the major targets identified by the innate immune system. In general, PRRs that sense nucleic acids are divided into membrane-bound Toll-like receptors (TLRs), cytosolic DNA sensors, and RNA sensors.

Membrane-bound TLRs recognize dsRNA, ssRNA, or unmethylated CpG DNA in the endosomal lumen, initiating signaling axes that culminate in the activation and nuclear translocation of transcription factors including interferon (IFN)-regulatory factor 3 (IRF3), interferon regulatory factor 7, and/or NF-κB (consisting of p65 and p50), to stimulate the transcription of specific genes such as type I interferon (IFN-I), and proinflammatory cytokine genes (83) (Fig. 2) .

Nucleic acid-sensing TLRs are expressed and function mostly in human immune cells. In addition, there are more general cytosolic DNA and RNA sensors that are ubiquitously expressed that can activate innate immune responses in response to viral infection.

Cytoplasmic RNAs derived from pathogens are mainly detected by retinoic acid-inducible gene I (RIG-I) or by melanoma differentiation-associated gene 5 (84) . This then leads to the stimulation of mitochondrial antiviral signaling protein on the mitochondrial membrane to activate IRF3 or NF-κB (p50/p65) and promote their nuclear translocation to induce the production of IFN-I and other antiviral molecules such as inflammatory cytokines (85) (Fig. 2 ). In addition, cyclic GMP-AMP synthase (cGAS) recognizes cytosolic dsDNA, either derived from DNA viruses or generated through the reverse transcription of retrovirus RNA genomes, and activates the production of cyclic dinucleotide GMP-AMP (cGAMP) from ATP and GTP (86) (87) (88) (89) . Being a small molecule, cGAMP not only activates downstream signals in the infected cell but also is packaged into new virions, where it can activate signals in subsequently infected cells (90) (91) (92) (93) . cGAMP binds to stimulator of IFN genes (STING), causing its relocalization from the ER to the ER-Golgi intermediate compartment and the Golgi complex. There, STING recruits kinases to activate IRF3 and NF-κB (p50/p65), which go on to activate transcription of IFN-I and proinflammatory cytokine genes (94-97) (Fig. 2) .

Once induced, newly synthesized IFN-I then functions via autocrine and paracrine signaling by directly binding to the interferon I receptor at the cell surface to initiate signaling, which in turn leads to the phosphorylation of signal transducer and activator of transcriptions (STATs) and the formation of STAT1/STAT2 heterodimer. The heterodimer further recruits interferon-regulatory factor 9 (IRF9) to form the interferonstimulated gene factor 3 (ISGF3) complex. The ISGF3 complex then rapidly translocates into the nucleus in an importindependent manner and binds to IFN-stimulated response elements of IFN-stimulated genes to activate their transcription (98) (Fig. 2) . Consequently, this stimulates the production of proteins that establish a robust immune response to repress the replication and assembly of pathogens (99, 100). . Upon recognition of pathogen-derived nucleic acids, all the PRRs initiate distinct signaling cascades that culminates in the activation and nuclear translocation of transcription factors, including IFN-regulatory factor 3 (IRF3), IRF7, and/or NF-κB (consisting of p65 and p50), to stimulate the transcription of specific genes, such as type I interferon (IFN-I), and proinflammatory cytokine genes. IFN-I then initiates antiviral signaling in the infected cell and neighboring cells by directly binding to the interferon I receptor (IFNAR) at the cell surfaces, which culminates in the expression of numerous interferon-stimulated genes to repress the replication and assembly of pathogens. cGAMP, cyclic dinucleotide GMP-AMP; cGAS, cyclic GMP-AMP synthase; ER, endoplasmic reticulum; IFN-I, type I interferon; IFNAR, IFN-I receptor; ISGF3, IFN-stimulated gene factor 3; ISRE, interferon-stimulated response element; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; RIG-I, retinoic acid-inducible gene I; STAT, signal transducer and activator of transcription; STING, stimulator of IFN genes; TLR, Toll-like receptor. The innate immune system has been extensively reviewed elsewhere (101) (102) (103) , so in the next section, we will discuss how these systems interface with the nuclear pore complex. As described previously, during the innate antiviral immune response, the production of IFNs, proinflammatory cytokines, and IFN-stimulated genes depends on the nuclear translocation of key innate immunity signal transducers. Unsurprisingly, signal transducers, such as IRF3, NF-κB (p50/p65), and STATs, interact with distinct Nups and/or nuclear transport receptors in order to traffic from the cytoplasm to the nucleus through nuclear pore complexes in response to the activation of PRRs (Table 1) .

IRF3 is a key transcription factor employed by various innate immunity pathways including RIG-I-like receptors, cGAS/STING signaling, and TLR3 signaling. It turns on the transcription of IFN-I genes in response to the activation of PRRs. To date, three nuclear transport receptors, importin-β1, importin-α3, and importin-α4, are known to promote IRF3 nuclear transport (104, 105) ( Table 1) .

NF-κB (p50/p65) is another crucial downstream signal transducer that transcriptionally activates IFN-I and proinflammatory cytokines upon PPR activation. It is imported into the nucleus by importin-β1, importin-α3, and importin-α4 (104-106) and requires the Nups Nup88, Nup214, Nup98, Nup153, RanBP2/Nup358, and POM121. The close link between nuclear porins and NF-κB appears to be ancient as it is conserved in Drosophila (107) (108) (109) (110) (111) . Interestingly, several chromosome translocation mutations result in the formation of fusion proteins involving Nups and a diverse set of proteins, which often impact the nucleocytoplasmic transport of NF-κB (p50/p65) and the activation of innate immune responses (Table 1) . NF-κB activity can be inhibited by CRM1, which mediates p65 nuclear export (112) . Recently, it has been suggested that overexpression of Nup62 stabilizes overexpressed Nup88 and its interaction with NF-κB (p65) to induce inflammatory signaling (113). Another recent study revealed that POM121 inhibits the nuclear translocation of phosphorylated p65 (phos-p65) and consequently impairs the macrophage inflammatory response (114) . Another report suggested that RanBP2/Nup358, which is one of the main components of the cytoplasmic filaments on the nuclear pore complex, and Nup153, which is part of the nuclear pore basket, formed a complex (RanBP2/Nup358-RanGDP-Nup153-IκBα-SUMO) in response to tumor necrosis factor α (TNF-α) stimulation. This complex facilitates the nuclear import of IκBα, allowing its binding to NF-κB (p50/p65). IκBα binding, in turn, masks the nuclear localization signal and the DNA-binding domain of NF-κB (p50/p65), thus downregulating innate immune responses (115) .

The nucleocytoplasmic trafficking of STATs (such as STAT1 and STAT2) plays a central role in activating IFNstimulated gene expression to repress viral replication and Table 1 The interaction of Nups or nuclear transport receptors with signal transducers of innate immunity

Nups/nuclear transport receptors Roles of nuclear pore-associated proteins in innate immune responses References

The main nuclear import receptor for IRF3 (104) Importin-α3 and importin-α4

Promoting nuclear import of IRF3 (105) NF-κB Importin-β1 The main nuclear import receptor for NF-κB (p65) (104) Importin-α3 and importin-α4

Promoting nuclear import of NF-κB ( 105, 106) Nup214-Nup88 complex Promoting the translocation of NF-κB (p65) from the cytoplasm to the nucleus (107, 109)

Stabilizing Nup88 and its interaction with NF-κB (p65) to induce inflammatory responses (113)

Inhibiting NF-κB activation by tethering the complex, including p65 and its inhibitor IκB, in the nucleus (108) Nup98-HOXA9 and Nup98-DDX10 Causing nuclear accumulation of NF-κB (p65), thus promoting NF-κB-mediated transcription (110) Nup98-IQCG Inhibiting the CRM1-mediated nuclear export of p65, thus enhancing the transcriptional activity of NF-κB

Inhibiting phosphorylated p65 (phos-p65) nuclear translocation, thus the macrophage inflammatory response (114) Nup153 and RanBP2/Nup358 Promoting IκBα nuclear import and subsequently terminating NF-κB activation (115) STATs (including STAT1 and STAT2) Importin-α3 Promoting the nuclear import of unphosphorylated STAT2/ IRF9 complex (130) Importin-α4 Promoting the nuclear import of unphosphorylated STAT2/ IRF9 complex (130) Importin-α5 Promoting the nuclear import of activated STAT1 and STAT2 (124, 125) Importin-α6 Promoting the nuclear import of activated STAT1 and STAT2

Importin-α7 Promoting the nuclear import of activated STAT1 and unphosphorylated STAT2/IRF9 complex (125, 130) Nup153 and Nup214

Promoting the nucleocytoplasmic translocation of latent STAT1 (116, 117) CRM1 Promoting the nuclear export of the unphosphorylated STAT1 and STAT2 (130) JBC REVIEWS: Nuclear pores, the innate immune response, and viruses assembly. In general, this process is accomplished via two distinct pathways. In the first, tyrosine-phosphorylated STAT dimers utilize importins to enter the nucleus upon cytokine stimulation. In the second pathway, latent unphosphorylated STATs employ karyopherin-independent and energy-free translocation mechanisms by directly interacting with FG-Nups without cytokine stimulation (116) (117) (118) . To date, several transport receptors and Nups have been shown to contribute to the nucleocytoplasmic transport of phosphorylated or unphosphorylated STATs (Table 1) . Upon IFN-I stimulation, both STAT1 and STAT2 are phosphorylated by Janus kinases and subsequently form a STAT1/STAT2 heterodimer. During heterodimer formation, STAT1 undergoes a conformational change that exposes a dimer-specific nuclear localization signal within its DNAbinding domain (119, 120) . Unlike conventional NLSs, which binds to importin-α (121) (122) (123) , this dimer-specific nuclear localization signal interacts with importin-α5 (124), importin-α6, and importin-α7 (125) , which then facilitates the nuclear translocation of the STAT1/STAT2/IRF9 complex (also known as the ISGF3 complex). In the nucleus, the ISGF3 complex binds to the IFN-stimulated response element promoter site to activate the transcription of various IFNstimulated genes. In addition, the binding of STAT1 to target DNA releases importin-α5 back to the cytoplasm for recycling (120, 126) .

One important concept that has emerged from the literature is that upon cytokine stimulation, the amount of nuclear accumulated STATs is often influenced by their nuclear retention rather than by the rate of their nuclear import (117) . It was observed that phosphorylated STAT1 can reside in the nucleus for around 30 min, and that the duration of its nuclear accumulation is affected by several phosphatases, such as 45-kDa T cell protein tyrosine phosphatase splice variant and SH2 domain-containing protein tyrosine phosphatase 2 (127) (128) (129) . Once dephosphorylated, STAT1 interacts with CRM1 via an exposed leucine-rich NES in its DNA-binding domain and in turn is exported back to the cytoplasm for subsequent activation-inactivation cycles (130) .

It was assumed that latent unphosphorylated STATs are trapped in the cytoplasm and do not shuttle in and out of the nucleus in resting cells. However, this idea has been challenged by several studies (116, 117, 131) . It should be noted that only a third of all the STAT1 protein is tyrosine phosphorylated at any given time during cytokine stimulation (127) . Although the conventional STAT1 nuclear localization signal requires phosphorylation to be active, unphosphorylated STAT1 still shuttles between cytosol and nucleus by directly binding to FG-Nups like Nup153 and Nup214 in a cytokine-independent manner (116, 117) .

STAT2 is another critical transcription factor in the IFN-I signaling pathway. Unlike other STATs, STAT2 is constitutively bound by the transcriptional activator IRF9. Upon IFN-I stimulation, phosphorylated STAT2 joins the ISGF3 complex and is transported into the nucleus as described previously. Thus, STAT1 is essential for the nuclear translocation of activated STAT2 (130) . Like STAT1, the recycling of STAT2 to the cytoplasm is catalyzed by its dephosphorylation by 45-kDa T cell protein tyrosine phosphatase splice variant and SH2 domain-containing protein tyrosine phosphatase 2. This causes the dissociation of STAT2/IRF9 from both STAT1 and the DNA. STAT2, which has its own nuclear export sequence, is then ferried out of the nucleus by CRM1. Like STAT1, STAT2 is believed to translocate into the nucleus even when it is unphosphorylated. However, unlike other STAT family members, this is not mediated by STAT2 directly, but rather its binding partner IRF9 (132) , suggesting that the nuclear translocation of the unphosphorylated STAT2 differs from that of unphosphorylated STAT1. Indeed, the import of STAT2 is dependent on IRF9 interactors, which include importin-α3, importin-α4, and importin-α7 (130) .

The interaction of viruses with nuclear pore proteins and nuclear transport receptors As discussed previously, the nucleocytoplasmic shuttling of signal transducers is regulated by distinct nuclear pore proteins and nuclear transport receptors. This regulation is critical for the host innate immune response upon viral infection. Therefore, it is not surprising that different viruses subvert the nucleocytoplasmic transport machinery to evade antiviral innate immunity. In the next sections, we discuss different viral proteins that interact and interfere with nuclear pore complexes and nuclear transport receptors, organized by viral families (summarized in Table 2 ).

Members of herpesviruses belong to Herpesviridae, which is a large family of dsDNA viruses that cause diseases in a wide range of hosts, including humans. There are nine herpesvirus types known to infect humans, including herpes simplex viruses (HSVs) type 1 and 2 (HSV-1 and HSV-2 or human herpesvirus 1 [HHV-1] and HHV-2), varicella-zoster virus (or HHV-3), Epstein-Barr virus (EBV or HHV-34), human cytomegalovirus (or HHV-5), HHV-6A and HHV-6B, HHV-7, and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8).

Most humans are infected with HSV-1, a member of alphaherpesvirus subfamily, which causes clinical symptoms, such as cold sores, in roughly one-third of all humans.

It has been observed that certain proteins encoded by HSV-1 interact with distinct nuclear pore proteins and nuclear transport receptors. The capsid (CA)-tethered tegument protein pUL36, and the minor CA protein pUL25, binds to RanBP2/Nup358 and Nup214, respectively, to dock the viral capsids at the cytoplasmic face of the nuclear pore, which subsequently facilitates the uncoating and release of the viral genome into the nucleus (133) (134) (135) (136) . pUL25 may have other functions, as viruses bearing a mutant form of this protein did not efficiently trigger cGAS signaling in infected cells. This mutation did not affect the attachment of CA to the nuclear pores but instead significantly delayed the expression of viral proteins (137) . It has also been reported that HSV-1 infection inhibits Nup153 expression (138) and alters its subcellular localization, sending this nuclear basket protein to the cytoplasm (139) . This observation suggests that HSV-1 interferes with nuclear import by repressing Nup153 (140) . ICP27 is another HSV-1 protein that interacts directly with Nup62 and blocks host protein import via importin-α, importin-β1, and importin-β2 nuclear import pathways (141) . In addition, ICP27 interacts with both the RNA export receptor TAP/NXF1 and the TREX complex adaptor protein Aly/REF, to preferentially export HSV-1 RNA over endogenous mRNAs (142) (143) (144) . Moreover, ICP27-like proteins encoded by other related herpesviruses, including human cytomegalovirus, KSHV, EBV, varicella-zoster virus, also facilitate nuclear export of viral mRNAs (145) (146) (147) (148) (149) .

The gamma-herpesvirus EBV also modulates nucleocytoplasmic transport. One of its proteins, BGLF4, is a serinethreonine protein kinase that directly binds and phosphorylates Nup62 and Nup153 to modulate nuclear pore complex organization (150, 151) . Consequently, BGLF4 blocks general nuclear import by impairing importin-β1 nuclear targeting, while simultaneously facilitating the nuclear import of certain EBV lytic proteins (151) .

Even though herpesviruses contain proteins that interact with nuclear pore complexes and nuclear transport receptors (as described previously), whether these interactions engage in the regulation of host innate immunity is unknown.

The family Adenoviridae is a large group of nonenveloped dsDNA viruses that infect a broad range of vertebrate hosts, including humans, and cause diseases, such as respiratory, gastrointestinal, urogenital, and ocular diseases. The entry of adenoviruses (AdVs) into the cell starts with the association of viral fiber proteins with host cell receptors (known as coxsackievirus AdV receptors) (152), followed by receptormediated endocytosis and virion escape into the cytoplasm (153) . Subsequently, these virions travel along microtubules through their interaction with the molecular motor dynein (154) . In this way, virions make their way to the nuclear envelope where they dock onto the cytoplasmic filaments of the nuclear pore by interacting with Nup214. Then the viral CA is disassembled in a kinesin-I-dependent manner (155), (286) Blocking the nuclear translocation of STAT1/ 2 releasing the viral genome into the nucleus. In addition, studies have indicated that AdVs displace cytoplasmic nuclear pore filament proteins (RanBP2/Nup358, Nup214, and Nup62) into the cytoplasm to increase nuclear envelope permeability and thereby facilitate the nuclear import of viral DNA (155) . In the nucleus, viral DNA is transcribed into adenoviral early mRNA, which is exported to the cytosol in a CRM1-dependent manner (156) , and adenoviral late transcripts, which are exported by the export receptor TAP/NXF1 (157) . Two adenoviral proteins, E1B-55K and E4orf6, not only inhibit NXF1-mediated host mRNAs export but also promote adenoviral late mRNA export by binding to the host protein E1B-AP5 (also known as hnRNPUL1), which interacts with NXF1 (158, 159) . The stepwise process of docking AdV CAs at the nuclear pore and uncoating of the virion to release viral genome into the nucleus may allow AdV to evade host antiviral innate immune responses by restricting viral DNA exposure in the cytoplasm. In addition, the disruption of host nucleocytoplasmic trafficking system may help interfere with the nuclear import of crucial factors involved in innate immunity (160) (161) (162) . Further studies are needed to determine whether the interaction between AdVs and host nucleocytoplasmic transport system contributes to viral evasion of the host innate immune response.

The family Poxviridae is a large group of dsDNA viruses that replicate in the cytoplasm and infect humans, vertebrates, and arthropods. Poxviruses are currently divided into 22 genera and 83 species. Among them, variola virus and vaccinia virus (VACV) are commonly known. Variola virus causes an acute contagious disease called smallpox and was responsible for a large number of deaths throughout human history. VACV, a lab-grown strain of poxvirus, was used as a live vaccine that helped to eradicate smallpox. VACV can stimulate a strong immune response and encodes a number of proteins that inhibit NF-κB activation to evade the host immune response (163) . Recently, it was shown that VACV protein A55 competes with NF-κB for importin-α1 binding, thereby preventing the nuclear import of NF-κB and inhibiting downstream gene transcription (164) (Fig. 4) .

Papillomaviruses (Papillomaviridae family) are a large family of small, nonenveloped, and icosahedral DNA viruses with a single molecule of 8 kb double-stranded circular DNA (165) . Human papillomavirus (HPV) includes low-risk HPVs, such as HPV-6 and HPV-11, causing benign exophytic condylomas, and high-risk HPVs, such as HPV-16, HPV-18, HPV-31, and HPV-45, which are associated with anogenital cancers, oropharyngeal cancers, and skin cancers (166) .

To date, the L1 major and L2 minor CA proteins of HPV-11 and HPV-16 have been revealed to interact with nuclear transport receptors. The HPV-11 L1 protein binds to importin-α1 and enters into the nucleus through the classical importin-α1/β1-mediated import system (167) . In addition, L1 from both HPV-11 and HPV-16 binds to importin-β2 and importin-β3, inhibiting their nuclear import activities (167) . The L2 minor CA protein of HPV-16 is transported into the nucleus by interacting with either importin-β2, importin-β3, or the importin-α1/importin-β1 heterodimer (168) . Although HPV-11 and HPV-16 associate with host nuclear import pathways, whether these interactions subvert host antiviral immune systems remain unknown.

Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses under the family of Coronaviridae. CoV genomes are approximately 30 kb with the first twothirds of the genome encoding two large polyproteins important for replicase function and the last third of the genome encoding multiple structural and accessory proteins. CoVs are divided into four genera named alpha-, beta-, gamma-, and delta-coronavirus (169) and can infect a wide range of hosts, such as bats, birds, mice, dogs, as well as humans (170, 171) . Among these, three novel beta-CoVs, including severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV2, are highly pathogenic in humans, causing worldwide outbreaks and pneumonia in the past 2 decades (172) (173) (174) . According to the coronavirus disease 2019 (COVID-19) map from Johns Hopkins University, SARS-CoV2 has infected over 160 million individuals globally and has caused 3.4 million deaths by mid-May 2021. In addition, four CoVs are responsible for up to 20% of all severe cases of the common cold (175) .

It is well known that human CoVs have evolved mechanisms to evade the host antiviral innate immunity. Certain proteins encoded by the three highly pathogenic human CoVs can antagonize host innate immune response by interacting with distinct nuclear pore proteins or nuclear transport receptors, which disrupt the nuclear transport of critical factors in innate immune signaling pathways. More specifically, the viral ORF6 protein of SARS-CoV inhibits IFN signaling by interacting with importin-α1 and importin-β1, tethering them to the rough endoplasmic reticulum/Golgi membrane, thus blocking the nuclear translocation of STAT1 without affecting its phosphorylation (176, 177) (Fig. 3) . Likewise, during MERS-CoV infection, the accessory protein 4b of MERS-CoV disrupts NF-κB nuclear translocation by outcompeting it for importin-α4 binding (178) (Fig. 4 ).

An interaction map of SARS-CoV2 proteins revealed that they associate with human proteins involved in several biological processes, including the innate immune response (179) . In particular, the nonstructural proteins (NSPs) 13 and 15, and ORF9b, bind to components of the IFN pathway and the NF-κB pathway. Other factors bind to the nucleocytoplasmic transport machinery, including NSP4 (which interacts with GP210), NSP9 (which associates with Nup54, Nup58, Nup62, Nup88, and Nup214), NSP15 (which binds to NTF2), and ORF6 (which interacts with the Nup98-RAE1 complex) (179) . Indeed, this last interaction has been confirmed by several JBC REVIEWS: Nuclear pores, the innate immune response, and viruses inhibits IFN signaling by interacting with importin-α1 and importin-β1, tethering them to the endoplasmic reticulum-Golgi membrane, thus blocking the nuclear translocation of STAT1 without affecting its phosphorylation. SARS-CoV2 ORF6 also blocks STAT1 nuclear translocation by interacting with the Nup98-RAE1 complex and disrupts the interaction between Nup98 and importin-β1/importin-α1/PY-STAT1 complex, thus preventing the docking of this complex at the nuclear pore. During HCV infection, viral NS3/4A complex binds to and cleaves importin-β1, which in turn blocks the nuclear translocation of STAT1 to restrict host antiviral immune response. VP24 of EBOV interacts with importin-α5, importin-α6, and importin-α7 at the regions where PY-STAT1 binds, and this prevents the formation of importin-α/PY-STAT1 transport complex, thereby blocking the nuclear import of activated STAT1 to counteract IFN signaling. In addition, HBV polymerase prevents the nuclear localization of STAT1/2 and the expression of interferon-stimulated genes by inhibiting importin-α5. . Viruses interfere with host IRF3 or NF-κB signaling by subverting their nuclear transport. During VACV infection, protein A55 prevents NF-κB nuclear translocation and inhibits NF-κB-dependent gene transcription by interacting with importin-α1 and disturbing the interaction between NF-κB and importin-α1. The accessory protein 4b of MERS-CoV disrupts NF-κB nuclear translocation by outcompeting it for importin-α4 binding and consequently interferes with NF-κB-dependent innate immune response. A complex of NS3/4A from HCV binds to and cleaves importin-β1, which in turn blocks the nuclear translocation of IRF3 and NF-κB-p65 to restrict host antiviral immune response. JEV NS5 protein competes with NF-κB-p65 and IRF3 for importin-α3 and importin-α4 binding and thus suppressing host innate immunity. HTNV nucleocapsid (N) protein interacts with importin-α1, importin-α2, and importin-α3, to block NF-κB nuclear translocation and inhibit NF-κB activity. In addition, HIV-1 viral protein R interacts with importin-α5 to prevent the nuclear translocation of IRF3 and NF-κB after immune activation. HCV, hepatitis C virus; HTNV, Hantaan virus; IRF3, IFN regulatory factor 3; JEV, Japanese encephalitis virus; MERS-CoV, Middle East respiratory syndrome coronavirus; VACV, vaccinia virus; Vpr, viral protein R.

other groups (180) (181) (182) (183) and was shown to disrupt bidirectional nucleocytoplasmic transport, likely inhibiting host response to viral infection (183) . This interaction also blocks nuclear translocation of STAT1 to antagonize IFN signaling (181) . Since RAE1 plays a role in mRNA export, ORF6 also alters the mRNA export and expression of innate immunity proteins. Aside from Nup98-RAE1 complex, ORF6 also interacts with many other key members of the nuclear pore machinery, including Nups, such as RanBP2/Nup358, Nup160, Nup188, Nup210, Nup37, and Nup93, importins, such as importin-5 (also known as importin-β3), importin-8, RanBP6, and importin-β1, exportins, such as CRM1 and exportin-T (also known as XPO3), as well as spliceosome components, such as THO complex subunit 3, a member of TREX complex known for splicing-coupled mRNA export (182) .

In addition, it was observed that SARS-CoV2 infection resulted in a significant reduction in RanBP2/Nup358 protein level, which was assumed to repress NF-κB activation as discussed previously (115, 184) . It is also known that SARS-CoV2 infection leads to the development of "cytokine storms" in most patients with severe COVID-19, in which immune cells and nonimmune cells secrete excessive amounts of cytokines, such as interleukin-6 (IL-6), TNF-α, and cause serious damage to hosts (185) (186) (187) (188) . In general, the hyperactivation of the NF-κB pathway is one of the major mechanisms leading to the phenotype of cytokine storms. SARS-CoV2 infection was shown to stimulate the IL-6 amplifier by activating both NF-κB and STAT3, which subsequently lead to the hyperactivation of NF-κB by STAT3, and the induction of multiple inflammatory and autoimmune diseases (189, 190) . Interestingly, mutations in RanBP2/Nup358 are also known to cause cytokine storms in response to influenza infection, and this is likely because of alterations in its ability to sumolyate proteins (see Orthomyxovirus section later). Indeed, sumoylation of NF-κB or STAT1 has been shown to inhibit their activation (191) (192) (193) . Although it remains unclear whether RanBP2/Nup358 engages in the sumoylation of NF-κB or STATs to repress antiviral innate immune responses, the aforementioned information suggests that RanBP2/Nup358 may play a critical role in the induction of cytokine storms by SARS-CoV2 infection. Further studies focusing on the crosstalk between RanBP2/Nup358, innate immunity, and SARS-CoV2 may help us develop novel drug targets and antiviral approaches against SARS-CoV2.

The Picornaviradae family is a group of nonenveloped, single-stranded, positive-sense RNA viruses that infect vertebrate hosts, including mammals and birds, and cause diseases, including poliomyelitis, paralysis, meningitis, and hepatitis. Picornaviruses are currently divided into 47 genera including the notable genera Enterovirus and Cardiovirus. It has been found that infection of human rhinovirus (HRV) and poliovirus (PV) in the Enterovirus genus and encephalomyocarditis virus (EMCV) and Theiler's murine encephalomyelitis virus (TMEV) in the Cardiovirus genus results in alterations in the nuclear pore complex composition and nucleocytoplasmic transport pathways (7, 160) . The proteases 3C pro and 2A pro encoded by HRV and PV, and leader (L) protein encoded by EMCV and TMEV, which processes a single viral polyprotein into several proteins, are found to disrupt nucleocytoplasmic trafficking. More specifically, 2A pro from PV mediates the proteolytic degradation of Nup62, Nup98, and Nup153, whereas HRV 2A pro cleaves Nup98 and Nup62 (194) (195) (196) (197) (198) . In addition, 3C pro and its precursor 3CD from HRV were shown to target Nup62, Nup153, Nup214, and Nup358 for proteolysis (199, 200) . The degradation of Nups mediated by protease 3C pro and 2A pro results in an increase in the bidirectional permeability of nuclear envelope (201, 202) and the disruption of nuclear import pathways mediated by importin-α/importin-β1 and importin-β2/transportin-1 (195, 197) . However, the mechanisms employed by cardioviruses like EMCV and TMEV, which lack a 2A-like protease, are quite different. The L protein from EMCV binds tightly to, and interferes with, the activity of Ran-GTPase and promotes the hyperphosphorylation of Nup62, Nup153, and Nup214. This results in the cytoplasmic accumulation of nuclear proteins by increasing nuclear envelope permeability and altering protein export (203) (204) (205) . In addition, TMEV L protein prevents the nuclear export of most mRNAs, likely by promoting Nup98 phosphorylation (203) (204) (205) . Overall, the modulation of nucleocytoplasmic trafficking by picornaviruses may contribute to its subversion of host antiviral innate immune responses.

Members of the Flaviviridae family are divided into four genera, including genus Flavivirus, Hepacivirus, Pegivirus, and Pestivirus. They are mainly transmitted through arthropod vectors, such as ticks and mosquitoes. Several important human pathogens in this virus family cause health challenges worldwide, and examples include the yellow fever virus, West Nile virus, dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), and tickborne encephalitis virus. The genome of each flavivirus member consists of a monopartite, linear, single-stranded, and positive polarity RNA molecule, which encodes a single polyprotein cleaved by both host and viral proteases into three structural (C, E, and prM) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins.

Several NSPs, such as NS2B, NS3, NS3/4A, NS5, have been found to associate with the nuclear pore complex and/or nuclear transport receptors to modulate nucleocytoplasmic transport pathways. During DENV infection, NS5 is transported into the nucleus by interacting with importin-α/β or by directly binding to importin-β. However, NS3 was shown to compete with NS5 for binding to importin-α/β, and this may reduce nuclear import of the latter, which may play a role in viral RNA processing in the cytoplasm (206) . In addition, the DENV NS3 has protease activity and has been shown to degrade Nup153, Nup98, and Nup62 (207) . Likewise, ZIKV NS3 mediates the degradation of Nup98, Nup153, and TPR (207) . Moreover, ZIKV infection inhibits the ubiquitinproteasomal degradation of importin-α7, thereby increasing its level, which in turn promotes viral replication (208) . In addition, it has been shown that a complex composed of NS3 and its cofactor NS4A from HCV, termed NS3/4A, binds to and cleaves importin-β1, which in turn blocks the nuclear translocation of STAT1, IRF3, and NF-κB-p65 and restricts host antiviral immune response (104, 209) (Figs. 3 and 4) . In JEV, the NS5 protein was shown to compete with NF-κB-p65 and IRF3 for importin-α3 and importin-α4 binding and thus suppressing host innate immunity (105) (Fig. 4) .

Another way in which flaviviruses, especially HCV, evade the immune system is to replicate in membrane-delimited vesicles in the cytoplasm, termed viral factories (210) . These structures prevent the detection of viral genomes by various innate immune pathways. Viral factories resemble mininuclei in that their delimiting envelope is derived from the ER, and any transport between the factory and cytosol must pass through nuclear pore-like structures that likely contain several Nups. In those formed by HCV, these pore-like structures contain Nup153, RanBP2/Nup358, Nup155, Nup98, and Nup53 (211, 212) . Similar viral factories are thought to be important for the replication of VACV (213) where the putative pores contain Nup62 and RanBP2/Nup358 (214, 215) . Other viruses that use viral factories that resemble mininuclei with nuclear pore-like structures include various flaviviruses, such as ZIKV, DENV, and West Nile virus (216) (217) (218) .

In summary, flaviviruses employ several distinct mechanisms to disrupt the nuclear transport of important cellular factors involved in immunity and consequently dampen host antiviral response.

The Filoviridae family is a group of single-stranded negative-sense RNA viruses, which is currently divided into four genera including genus Cuevavirus, Dianlovirus, Ebolavirus, and Marburgvirus. Among them, Ebola virus (EBOV) and Marburg virus are two commonly known filoviruses, which cause periodic outbreaks of severe hemorrhagic fever in humans, with high fatality rates of up to 90% (219, 220). During EBOV infection, the viral protein VP24 interacts with importin-α5, importin-α6, and importin-α7 at the regions where tyrosine-phosphorylated STAT1 (PY-STAT1) usually binds. This prevents the importin-α/PY-STAT1 transport complex formation and thus blocks the nuclear import of activated STAT1 to counteract IFN-α/β and IFN-γ signaling (125, (221) (222) (223) (Fig. 3) . Thus, like other viruses discussed previously, EBOV can evade host antiviral innate immunity by interfering with nuclear transport pathways.

The Orthomyxoviridae family includes influenza viruses that are divided into four types (A, B, C, and D), where influenza A viruses (IAVs) cause seasonal epidemics, commonly known as the flu (224) . Upon infection, the viral particles are imported into the nucleus of host cells via the importin-α/β system for transcription and replication (225) . The influenza viruses make use of CRM1 for the export of progeny viral particles (226) . It is believed that influenza viruses outcompete host CRM1 substrates by localizing viral particle export complexes in close proximity to regulator of chromosome condensation 1. Thus, once RanGTP-bound CRM1 is generated, the viral particles gain preferential access to CRM1 before it diffuses to bind host cellular substrates, and as a result, the host CRM1-mediated export is impaired (227) .

During influenza infection, the viral NSP NS1 protein is a major player for the viruses to evade innate immune responses. In the cytoplasm, NS1 inhibits the activation of RIG-I receptor signaling and prevents induction of IFN-β through binding to RIG-1 and the E3-ubiquitin ligase TRIM25 (228) (229) (230) (231) . In the nucleus, NS1 inhibits splicing and 3 0 -end processing of host mRNAs through its interaction with the U6 snRNP (232), the cleavage and polyadenylation specificity factor CPSF30 (233), and the poly(A)-binding protein PABP1 (234) . NS1 further alters host gene expression by forming an inhibitory complex with the host mRNA export machinery NXF1/NXT1, Rae-1, and E1B-AP5, thus blocking the export of host mRNAs encoding for antiviral factors such as RIG-1, or mRNAs regulated by IFN such as IFIT2 and IFIT3 (235, 236) . Besides sequestering host mRNA export machinery, influenza viruses also downregulate Nup98, which provides a docking site for the mRNA export factors at the nuclear pore, and this further inhibits the export of host antiviral mRNAs (235, 237) .

Interestingly, dominant mutations in RanBP2/Nup358 are associated with acute necrotizing encephalopathy 1 (ANE1), where patients suffer from elevated levels of cytokine production after viral infection, oftentimes by influenza viruses (238, 239) . These cytokine storms are typically restricted to the brain, unlike in COVID-19, where they are localized to the lung. How mutations in RanBP2/Nup358 contribute to disease remains unclear. Our recently published work suggests that RanBP2/Nup358 represses the translation of two ANE1associated cytokine mRNAs, IL-6 and TNF-α, by sumoylating argonaute proteins thereby enforcing microRNA-mediated silencing (240) . Our data indicate that argonautes initially interact with the IL-6 mRNA in the nucleus, and that after nuclear export, RanBP2-dependent sumoylation stabilizes argonaute binding to the mRNA as part of an mRNP remodeling event. It is thus possible that ANE1-associated mutations alter this remodeling event, which eventually leads to pathology, though further studies are needed. As a number of case studies have indicated that COVID-19 can sometimes result in ANE1-like cytokine storms in the brain (241) (242) (243) (244) (245) , it would be important to determine whether these patients have mutations in RanBP2/Nup358.

The vesicular stomatitis virus (VSV), a member of the Rhabdoviridae family, causes acute vesicular disease in rodents, cattle, swine, horses, and sometimes humans (246) . It is an enveloped, single-stranded, and negative-sense RNA virus that replicates in the cytoplasm (246) . VSV suppresses host JBC REVIEWS: Nuclear pores, the innate immune response, and viruses antiviral responses by the viral matrix (M) protein, which has been found to block host gene expression at the levels of transcription (247) (248) (249) , mRNA export (250) (251) (252) (253) , and translation (254, 255) . Since M protein lacks enzymatic activity, it is believed that it inhibits host gene expression by interacting with host factors and interfering with their functions. It has been shown that during VSV infection, M protein interacts with host proteins RAE1 and Nup98. While some studies showed that the interaction among M, RAE1, and Nup98 prevents bulk poly(A) mRNA export (250, 253) , another study found that this complex also binds to chromatin and partially mediates the ability of VSV to inhibit host transcription, without affecting host mRNA export or host translation in VSV-infected cells (252) . Though it is still unclear how exactly M protein inhibits host gene expression, it appears to suppress this process at multiple levels, and this helps VSV evade the immune system.

Bunyaviruses (Bunyaviridae family) are a large family of spherical and enveloped RNA viruses with a negative-sense and single-stranded RNA genome. Bunyaviruses are currently divided into five genera including genus Hantavirus, Nairovirus, Orthobunyavirus, Phlebovirus, and Tospovirus, which only infects plants. Many bunyaviruses can infect humans causing several mild to severe diseases. Unlike most bunyaviruses, which are arthropod borne, Hantaviruses are rodent borne. Hantaviruses were first discovered near the Hantaan River in Korea and now are found worldwide. Hantaviruses cause high fever, lung edema, as well as pulmonary failure in humans. Hantaan virus, a member of the Hantavirus genus, has been shown to inhibit NF-κB activity through the interaction between its nucleocapsid (N) protein and importin-α1, importin-α2, and importin-α3, and blocking NF-κB nuclear translocation (256) (Fig. 4) . Thus, Hantaan virus is another example that virus can manipulate host antiviral innate immunity by disrupting nuclear transport pathways.

HIV-1 belongs to the genus Lentivirus of the Retroviridae family and is an enveloped positive-strand RNA virus that causes AIDS. Upon infection, the HIV-1 virion delivers two single-stranded RNA genomes into the cytoplasm of host cells, which are then reverse transcribed into complementary DNA, associate with viral proteins and cellular machinery in the form of preintegration complex, and translocate into the nucleus for integration into the host genome (257) .

Viral proteins such as the M protein, integrase, viral protein R (Vpr) contain NLSs (258) (259) (260) (261) , and many studies have demonstrated their interaction with nuclear transport receptors, such as various importin-α isoforms (e.g., importin-α1, importin-α3, importin-α5) (262) (263) (264) (265) (266) (267) , importin-7 (266) , and transportin-3 (268) , which are important for the nuclear translocation of the preintegration complex. At later stages of HIV-1 infection, the Vpr helps recruit CRM1 via its NES to mediate the export of intron-containing viral transcripts (269) .

Many Nups have been indicated as important host cofactors for HIV-1 infection, including Nup62, Nup153, Nup98, Nup214, RanBP2/Nup358, and hCG1 (270) (271) (272) (273) (274) (275) (276) (277) (278) . These Nups have been shown to interact with various viral proteins to assist with nuclear import of the preintegration complex, viral DNA integration, and nuclear export of viral factors. Besides co-opting the host Nups and nuclear transport machinery, HIV-1 also blocks the nuclear import of hnRNP A1, A2, and D. These proteins then act in the cytoplasm to increase internal ribosome entry site-mediated translation of viral proteins (279, 280) .

Interestingly, it has been shown that the HIV-1 CA protein mutants N74D and P90A, which are unable to interact with CPSF6, RanBP2/Nup358, and cyclophilin A, end up triggering IFN production and ultimately prevent viral replication (281) . Thus, the CA protein's interaction with CPSF6, RanBP2/ Nup358, and cyclophilin A likely contributes to the evasion of immune sensors; however, the mechanism remains unclear. The authors proposed that the interaction between the CA protein and host factors may restrict viral complementary DNA production to the nuclear pore, allowing it to be rapidly imported into the nucleus and thus preventing the viral DNA from being detected by cytosolic sensors. Recently, it is found that the interaction of HIV-1 Vpr with importin-α5 prevents efficient recruitment and transport of transcription factors IRF3 and NF-κB into the nucleus after immune activation (282) (Fig. 4) . By targeting activated transcription factors, Vpr can promote HIV-1 replication in innate immune-activated cells, even when immune stimulation is caused by other PAMPs unrelated to HIV-1.

Viral hepatitis refers to a liver inflammation caused by viral infection, and the most common causes are the five unrelated hepatitis viruses A, B, C, D, and E. Hepatitis B virus (HBV) belongs to the Hepadnaviridae family and is a partially dsDNA virus that replicates through an RNA intermediate and integrates into the host genome (283) . Upon hepatitis B viral infection, its CA proteins become phosphorylated, which exposes the nuclear localization signal and allows for its interaction with importin-α/β and subsequent nuclear import (284, 285) . Though both mature and immature viral capsids are imported, only the mature capsids disintegrate and release their DNA genome into the host nucleus, whereas the immature capsids are arrested at the nuclear basket (285) . Nup153, which is localized to the nuclear basket, has been found to interact with the viral capsids, and knockdown of this protein increases the amount of genome release from immature capsids (286) . Thus, it is believed that Nup153 prevents premature release of genome, and this may be an essential step in the viral replication cycle.

HBV employs multiple strategies to evade immune response, and the viral polymerase is thought to play a major role. It has been shown that the hepatitis B viral polymerase can interact with heat shock protein 90 (287) and the DEADbox RNA helicase DDX3 (288) , which prevents the activation of pattern recognition receptor signaling and STING-mediated viral DNA sensing. Furthermore, the polymerase activity inhibits both importin-α5 and protein kinase C-δ and prevents the nuclear localization of STAT1/2 and the expression of IFN-stimulated genes (289) (Fig. 3) .

In sum, the nuclear transport of signal transducers, such as IRF3, NF-κB, and STATs, is mediated by different nuclear transport receptors and is indispensable for the activation of host antiviral innate immune responses. Although it remains unclear whether the disruption of nucleocytoplasmic transports by several viruses discussed previously interfere with the host innate immunity, the crosstalk between other viruses (such as SARS-CoV, MERS, HCV, JEV, EBOV, IAV, HIV-1, and HBV), nucleocytoplasmic trafficking pathways, and host antiviral innate immune responses suggest that such subversion of the nucleocytoplasmic transport systems may be a common immune evasion strategy by distinct viruses. Therefore, nucleocytoplasmic transport pathways are logical antiviral therapeutic targets.

To date, several drugs have been identified to target nucleocytoplasmic trafficking systems from high-throughput drug screening. A compound named quinoline carboxylic acid was discovered to restore mRNA export inhibition caused by influenza A viral protein NS1, through enhancing the expression of the nuclear transport receptor NXF1 (290) . Ivermectin, a small-molecule inhibitor of nuclear import, was shown to interfere with DENV-2 and HIV-1 infection by blocking the nuclear import of DENV-2 NS5 protein and HIV-1 integrase (291) . Beyond these two viruses, ivermectin was also able to inhibit infection caused by Venezuelan equine encephalitis virus (VEEV) (292) , AdV (293) , as well as ZIKV (294) , and potentially several alphaviruses, such as Chikungunya virus, Sindbis virus, and Semliki forest virus (295) . In addition, mifepristone, another inhibitor of importin α/βmediated import, has been shown to reduce nuclear-associated CA and viral titer of VEEV in a relevant mammalian cell line (292) and inhibit AdV infection (293) . Aside from nuclear import inhibitors, there are also nuclear export inhibitors, such as leptomycin B and verdinexor (KPT-335), that have been shown to interfere with viral infection. Indeed, leptomycin B was discovered to reduce viral titer of VEEV in a mammalian cell line (292) . Later, it was shown to inhibit the nuclear export of HIV-1 Rev protein (296) . Verdinexor was demonstrated to inhibit the infection of respiratory syncytial virus, VEEV, IAV, EBV, KSHV, AdV-5, as well as HPV-11 (297) (298) (299) (300) . More recently, studies revealed that selinexor, another nuclear export inhibitor that selectively binds CRM1, could be repurposed to directly target the interaction between the SARS-CoV-2 protein ORF6 and other host proteins such as Nup98-RAE1 (179, 182) . Although none of the drugs has been approved in clinical trials for treating viral infections, these studies show that the comprehensive understanding of the crosstalk between nucleocytoplasmic transport and host antiviral immune responses to viral infection, together with high-throughput drug screening, will contribute to the development of novel antiviral therapies in the future.

Author contributions-Q. S. and A. F. P. conceptualization; Q. S. and A. F. P. funding acquisition; Q. S., Y. E. W., and A. F. P. writingoriginal draft; Q. S., Y. E. W. and A. F. P. writing-review and editing; A. F. P. supervision.

Funding and additional information-The authors acknowledge financial support for this work from a Canadian Institutes of Health Research grant to A. F. P. (FRN 102725) , a startup grant for Highlevel Talents of Fujian Medical University (XRCZX2019019) and a Natural Science Foundation of Fujian Province, China (no. 2020J01604) to Q. S.

Conflict of interest-The authors declare that they have no conflicts of interest with the contents of this article.

Abbreviations-The abbreviations used are: AdV, adenovirus; ANE1, acute necrotizing encephalopathy 1; CA, capsid; cGAMP, cyclic dinucleotide GMP-AMP; cGAS, cyclic GMP-AMP synthase; CoV, coronavirus; COVID-19, coronavirus disease 2019; CRM1, chromosomal maintenance 1; DENV, dengue virus; EBOV, Ebola virus; EBV, Epstein-Barr virus; EMCV, encephalomyocarditis virus; ER, endoplasmic reticulum; FG-Nups, Nups that contain phenylalanine-glycine repeats; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV, human herpesvirus; hnRNP, heterogenous nuclear ribonucleoprotein; HPV, human papillomavirus; HRV, human rhinovirus; HSV, herpes simplex virus; IAV, influenza A virus; IFN, interferon; IFN-1, type I interferon; IL-6, interleukin-6; IRF3, interferon-regulatory factor 3; IRF9, interferon-regulatory factor 9; ISGF3, interferon-stimulated gene factor 3; JEV, Japanese encephalitis virus; KSHV, Kaposi's sarcoma-associated herpesvirus; L, leader protein; M, matrix protein; MERS, Middle East respiratory syndrome; mRNP, messenger ribonucleoprotein; NES, nuclear export signal; NLS, nuclear localization signal; NSP, nonstructural protein; NTF2, nuclear transport factor 2; Nup, nucleoporin; NXF1, nuclear RNA export factor 1; NXT1, NTF2-like export factor 1; PAMP, pathogen-associated molecular pattern; PRR, patternrecognition receptor; PV, poliovirus; RIG-I, retinoic acid-inducible gene I; SARS, severe acute respiratory syndrome; STAT, signal transducer and activator of transcription; STING, stimulator of IFN genes; TLR, Toll-like receptor; TMEV, Theiler's murine encephalomyelitis virus; TNF-α, tumor necrosis factor α; TPR, translocated promoter region; TREX, transcription export; VACV, vaccinia virus; VEEV, Venezuelan equine encephalitis virus; Vpr, viral protein R; VSV, vesicular stomatitis virus; ZIKV, Zika virus.. 

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The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human

TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture

TREX is a conserved complex coupling transcription with messenger RNA export

Nuclear export of messenger RNA

Nuclear export as a key arbiter of "mRNA identity" in eukaryotes

The DEAD-box protein Dbp5p is required to dissociate Mex67p from exported mRNPs at the nuclear rim

Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export

Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export

Single particle imaging of mRNAs crossing the nuclear pore: Surfing on the edge

Structure and function of the nuclear pore complex cytoplasmic mRNA export platform

Selective nuclear export of specific classes of mRNA from mammalian nuclei is promoted by GANP

The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores

Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery

Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery

Sem1 is a functional component of the nuclear pore complex-associated messenger RNA export machinery

The human TREX-2 complex is stably associated with the nuclear pore basket

Structural basis for binding the TREX2 complex to nuclear pores, GAL1 localisation and mRNA export

2020) TPR is required for the efficient nuclear export of mRNAs and lncRNAs from short and intron-poor genes

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

Gene architecture and sequence composition underpin selective dependency of nuclear export of long RNAs on NXF1 and the TREX complex

Approaching the asymptote? Evolution and revolution in immunology

The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors

Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5

MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response

Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses

Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects

Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

Viruses transfer the antiviral second messenger cGAMP between cells

Structure-function analysis of STING activation by c

Transmission of innate immune signaling by packaging of cGAMP in viral particles

) cGAS-Mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites

Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA

STING activation by translocation from the ER is associated with infection and autoinflammatory disease

STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation

The JAK-STAT pathway at twenty

Viral evasion and subversion of pattern-recognition receptor signalling

Intrinsic antiviral immunity

Innate immune detection of microbial nucleic acids

Detection of microbial infections through innate immune sensing of nucleic acids

Innate immune sensing and signaling of cytosolic nucleic acids

Importin β1 targeting by hepatitis C virus NS3/4A protein restricts IRF3 and NF-κB signaling of IFNB1 antiviral response

Japanese encephalitis virus NS5 inhibits type I interferon (IFN) production by blocking the nuclear translocation of IFN regulatory factor 3 and NF-κB

NF-κB is transported into the nucleus by importin α3 and importin α4

The nucleoporin Nup214 sequesters CRM1 at the nuclear rim and modulates NFκB activation in Drosophila

Leukemiaassociated Nup214 fusion proteins disturb the XPO1-mediated nuclearcytoplasmic transport pathway and thereby the NF-κB signaling pathway

Downregulation of nucleoporin 88 and 214 induced by oridonin may protect OCIM2 acute erythroleukemia cells from apoptosis through regulation of nucleocytoplasmic transport of NF-κB

Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins

Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG

A functional connection between RanGTP, NF-kappaB and septic shock

Overexpressed Nup88 stabilized through interaction with Nup62 promotes NFκB dependent pathways in cancer

POM121 inhibits the macrophage inflammatory response by impacting NF-κB P65 nuclear accumulation

A novel mechanism for NF-κB-activation via IκB-aggregation: Implications for hepatic Mallory-Denk-body induced inflammation

Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1

Nucleocytoplasmic shuttling of STAT transcription factors

STAT nuclear translocation: Potential for pharmacological intervention

Arginine/ lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5

Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α

Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha

Nuclear import: A tale of two sites

Diversification of importin-α isoforms in cellular trafficking and disease states

Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5

Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1

Nuclear export signal located within the DNA-binding domain of the STAT1tran-scription factor

The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase

Identification of a nuclear Stat1 protein tyrosine phosphatase

SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei

STAT2 nuclear trafficking

Cell type-specific and tyrosine phosphorylation-independent nuclear presence of STAT1 and STAT3

Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-α-stimulated transcription factor ISGF3

Herpes simplex virus replication: Roles of viral proteins and nucleoporins in capsid-nucleus attachment

Proteolytic cleavage of VP1-2 is required for release of herpes simplex virus 1 DNA into the nucleus

Herpesvirus capsid association with the nuclear pore complex and viral DNA release involve the nucleoporin CAN/Nup214 and the capsid protein pUL25

The UL25 gene product of herpes simplex virus type 1 is involved in uncoating of the viral genome

The C terminus of the herpes simplex virus UL25 protein is required for release of viral genomes from capsids bound to nuclear pores

Transcriptional response of a common permissive cell type to infection by two diverse alphaherpesviruses

Herpes simplex virus 1 envelopment follows two diverse pathways

RanGTP-mediated nuclear export of karyopherin α involves its interaction with the nucleoporin Nup153

Herpes simplex virus ICP27 protein directly interacts with the nuclear pore complex through Nup62, inhibiting host nucleocytoplasmic transport pathways

Efficient nuclear export of herpes simplex virus 1 transcripts requires both RNA binding by ICP27 and ICP27 interaction with TAP/NXF1

The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable

Herpes simplex virus ICP27 protein provides viral mRNAs with access to the cellular mRNA export pathway

Recruitment of the complete hTREX complex is required for Kaposi's sarcoma-associated herpesvirus intronless mRNA nuclear export and virus replication

A region of the Epstein-Barr virus (EBV) mRNA export factor EB2 containing an arginine-rich motif mediates direct binding to RNA

The UL69 transactivator protein of human cytomegalovirus interacts with DEXD/H-box RNA helicase UAP56 to promote cytoplasmic accumulation of unspliced RNA

Varicella-zoster virus IE4 protein interacts with SR proteins and exports mRNAs through the TAP/NXF1 pathway

The prototype γ-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway

Epstein-Barr virus protein kinase BGLF4 targets the nucleus through interaction with nucleoporins

BGLF4 kinase modulates the structure and transport preference of the nuclear pore complex to facilitate nuclear import of Epstein-Barr virus lytic proteins

HCAR and MCAR: The human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses

Stepwise loss of fluorescent core protein V from human adenovirus during entry into cells

Adenovirus recruits dynein by an evolutionary novel mechanism involving direct binding to pH-primed hexon

Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection

CRM1-dependent transport supports cytoplasmic accumulation of adenoviral early transcripts

Export of adenoviral late mRNA from the nucleus requires the Nxf1/tap export receptor

Control of mRNA export by adenovirus E4orf6 and E1B55K proteins during productive infection requires E4orf6 ubiquitin ligase activity

Adenovirus ubiquitin-protein ligase stimulates viral late mRNA nuclear export

Viral subversion of the nuclear pore complex

Uncoating of non-enveloped viruses

Viral appropriation: Laying claim to host nuclear transport machinery

Vaccinia virus immune evasion: Mechanisms, virulence and immunogenicity

Vaccinia virus BBK E3 ligase adaptor A55 targets importin-dependent NF-κB activation and inhibits CD8+ T-cell memory

Identification of proteins encoded by the L1 and L2 open reading frames of human papillomavirus 1a

Papillomaviruses causing cancer: Evasion from host-cell control in early events in carcinogenesis

The L1 major capsid protein of human papillomavirus type 11 interacts with kap β2 and kap β3 nuclear import receptors

The L2 minor capsid protein of human papillomavirus type 16 interacts with a network of nuclear import receptors

Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus

Middle East respiratory syndrome coronavirus (MERS-CoV): Announcement of the coronavirus study group

Coronavirus diversity, phylogeny and interspecies jumping

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

A new coronavirus associated with human respiratory disease in China

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Hosts and sources of endemic human coronaviruses

Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane

Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists

MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Virus-host interactome and proteomic survey reveal potential virulence factors influencing SARS-CoV-2 pathogenesis

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor

SARS-CoV-2 ORF6 disrupts bidirectional nucleocytoplasmic transport through interactions with Rae1 and Nup98

Re-analysis of SARS-CoV-2-infected host cell proteomics time-course data by impact pathway analysis and network analysis: A potential link with inflammatory response

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Dysregulation of immune response in patients with coronavirus

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

COVID-19: A new virus, but a familiar receptor and cytokine release syndrome

Pleiotropy and specificity: Insights from the interleukin 6 family of cytokines

NF-κB repression by PIAS3 mediated RelA SUMOylation

SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation

Stat1 and SUMO modification

RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage

Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition

Inhibition of nuclear import and alteration of nuclear pore complex composition by rhinovirus

Differential targeting of nuclear pore complex proteins in poliovirus-infected cells

Specific cleavage of the nuclear pore complex protein Nup62 by a viral protease

Rhinovirus 3C protease can localize in the nucleus and alter active and passive nucleocytoplasmic transport

Rhinovirus 3C protease facilitates specific nucleoporin cleavage and mislocalisation of nuclear proteins in infected host cells

Early alteration of nucleocytoplasmic traffic induced by some RNA viruses

Bidirectional increase in permeability of nuclear envelope upon poliovirus infection and accompanying alterations of nuclear pores

Leader-induced phosphorylation of nucleoporins correlates with nuclear trafficking inhibition by cardioviruses

A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport

Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein

A small region of the dengue virus-encoded RNA-dependent RNA

NS5, confers interaction with both the nuclear transport receptor importin-beta and the viral helicase

The nuclear pore complex: A target for NS3 protease of dengue and Zika viruses

Karyopherin alpha 6 is required for replication of porcine reproductive and respiratory syndrome virus and Zika virus

Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches

Targeting nuclear proteins for control of viral replication

Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication

Functional characterization of nuclear localization and export signals in hepatitis C virus proteins and their role in the membranous web

Vaccinia virus DNA replication occurs in endoplasmic reticulumenclosed cytoplasmic mini-nuclei

Human genome-wide RNAi screen reveals a role for nuclear pore proteins in poxvirus morphogenesis

Selective recruitment of nucleoporins on vaccinia virus factories and the role of Nup358 in viral infection

Ultrastructural characterization of Zika virus replication factories

Composition and three-dimensional architecture of the dengue virus replication and assembly sites

The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex

Ebola haemorrhagic fever

Pathogenesis of filoviral haemorrhagic fevers

Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling

Ebola virus VP24 binds karyopherin α1 and blocks STAT1 nuclear accumulation

Ebola virus VP24 targets a unique NLS-binding site on karyopherin5 to selectively compete with nuclear import of phosphorylated STAT1

The biology of influenza viruses

Nuclear import of influenza A viral ribonucleoprotein complexes is mediated by two nuclear localization sequences on viral nucleoprotein

Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1

Influenza virus ribonucleoprotein complexes gain preferential access to cellular export machinery through chromatin targeting

Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by RIG-I

Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus

Structural basis for a novel interaction between the NS1 protein derived from the 1918 influenza virus and RIG-I

The influenza NS1 protein modulates RIG-I activation via a strain-specific direct interaction with the second CARD of RIG-I

The influenza virus NS1 protein binds to a specific region in human U6 snRNA and inhibits U6-U2 and U6-U4 snRNA interactions during splicing

Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs

Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3'-end processing machinery

Structural basis for influenza virus NS1 protein block of mRNA nuclear export

Influenza virus targets the mRNA export machinery and the nuclear pore complex

Human cellular protein nucleoporin hNup98 interacts with influenza A virus NS2/nuclear export protein and overexpression of its GLFG repeat domain can inhibit virus propagation

Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2

Genetic acute necrotizing encephalopathy associated with RANBP2: Clinical and therapeutic implications in pediatrics

2021) RanBP2/ Nup358 enhances miRNA activity by sumoylating Argonautes

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: Imaging features

A first case of meningitis/encephalitis associated with SARS-coronavirus-2

Acute necrotizing encephalopathy associated with SARS-CoV-2 exposure in a pediatric patient

Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid

SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: A case report

Vesicular stomatitis virus: Re-inventing the bullet

Effect of vesicular stomatitis virus matrix protein on transcription directed by host RNA polymerases I, II, and III

Vesicular stomatitis virus matrix protein inhibits host cell-directed transcription of target genes in vivo

Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactivation of TFIID

VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway

Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus

Complexes of vesicular stomatitis virus matrix protein with host Rae1 and Nup98 involved in inhibition of host transcription

Vesicular stomatitis virus matrix protein inhibits host cell gene expression by targeting the nucleoporin Nup98

Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1

Ability of the matrix protein of vesicular stomatitis virus to suppress beta interferon gene expression is genetically correlated with the inhibition of host RNA and protein synthesis

Hantaan virus nucleocapsid protein binds to importin α proteins and inhibits tumor necrosis factor alpha-induced activation of nuclear factor kappa B

The HIV-1 passage from cytoplasm to nucleus: The process involving a complex exchange between the components of HIV-1 and cellular machinery to access nucleus and successful integration

A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells

Two nuclear localization signals in the HIV-1 matrix protein regulate nuclear import of the HIV-1 pre-integration complex

HIV-1 infection requires a functional integrase NLS

Mutagenic analysis of human immunodeficiency virus type 1 Vpr: Role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation

Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import

HIV-1 infection of nondividing cells through the recognition of integrase by the importin/ karyopherin pathway

Novel nuclear import of Vpr promoted by importin α is crucial for human immunodeficiency virus type 1 replication in macrophages

Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication

Interaction of human immunodeficiency virus type 1 integrase with cellular nuclear import receptor importin 7 and its impact on viral replication

Viral protein R regulates nuclear import of the HIV-1 pre-integration complex

Transportin-SR2 imports HIV into the nucleus

Inhibition of human immunodeficiency virus Rev and human T-cell leukemia virus Rex function, but not Mason-Pfizer monkey virus constitutive transport element activity, by a mutant human nucleoporin targeted to Crm1

Integrase interacts with nucleoporin NUP153 to mediate the nuclear import of human immunodeficiency virus type 1

The functionally conserved nucleoporins Nup124p from fission yeast and the human Nup153 mediate nuclear import and activity of the Tf1 retrotransposon and HIV-1 Vpr

Role of Nup98 in nuclear entry of human immunodeficiency virus type 1 cDNA

Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1

Global analysis of host-pathogen interactions that regulate early stage HIV-1 replication

Nucleoporins nup98 and nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev

The nuclear pore component Nup358 promotes transportindependent nuclear import

Contribution of host nucleoporin 62 in HIV-1 integrase chromatin association and viral DNA integration

Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration

Human immunodeficiency virus type 1 (HIV-1) induces the cytoplasmic retention of heterogeneous nuclear ribonucleoprotein A1 by disrupting nuclear import: Implications for HIV-1 gene expression

Differential effects of hnRNP D/AUF1 isoforms on HIV-1 gene expression

HIV-1 evades innate immune recognition through specific co-factor recruitment

HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB

Hepatitis B: The virus and disease

Phosphorylation-dependent binding of hepatitis B virus core particles to the nuclear pore complex

Nuclear import of hepatitis B virus capsids and release of the viral genome

Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket

Hepatitis B virus polymerase suppresses NF-κB signaling by inhibiting the activity of IKKs via interaction with Hsp90β

Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: Implications for immune evasion

Hepatitis B virus polymerase impairs interferon-αinduced STA T activation through inhibition of importin-α5 and protein kinase C-δ

Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication

Inhibition of adenovirus infection by mifepristone

A screen of FDA-approved drugs for inhibitors of Zika virus infection

Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses

Leptomycin B is an inhibitor of nuclear export: Inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and rev-dependent mRNA

Selective inhibitor of nuclear export (SINE) compounds alter new world alphavirus capsid localization and reduce viral replication in mammalian cells

Verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo

In vitro toxicity and efficacy of verdinexor, an exportin 1 inhibitor, on opportunistic viruses affecting immunocompromised individuals

Verdinexor (KPT-335), a selective inhibitor of nuclear export, reduces respiratory syncytial virus replication in vitro

Acknowledgments-The authors apologize to our colleagues whose work was not discussed adequately or cited owing to space limitations.