key: cord-0023596-qwj9j55w
authors: Lamotte, Laurie-Anne; Tafforeau, Lionel
title: How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity
date: 2021-11-19
journal: Viruses
DOI: 10.3390/v13112309
sha: 75031d9f62a9053d7520b86e34e1126e8f4e12d9
doc_id: 23596
cord_uid: qwj9j55w

Ubiquitination is a post-translational modification regulating critical cellular processes such as protein degradation, trafficking and signaling pathways, including activation of the innate immune response. Therefore, viruses, and particularly influenza A virus (IAV), have evolved different mechanisms to counteract this system to perform proper infection. Among IAV proteins, the non-structural protein NS1 is shown to be one of the main virulence factors involved in these viral hijackings. NS1 is notably able to inhibit the host’s antiviral response through the perturbation of ubiquitination in different ways, as discussed in this review.

Ubiquitin is a small 8.5 kDa protein consisting of 76 amino acids, expressed in almost every cell type and largely conserved through eukaryotes. The binding of the C-terminal ubiquitin end to the ε-amino group of lysine (K) residue on a protein substrate is called ubiquitination. Ubiquitination is one of the best described post-translational modifications and it regulates, among other things, targeted protein localization, function, cellular trafficking, and degradation by the 26S proteasome [1, 2] . Specific substrate ubiquitination requires a three-step enzymatic cascade involving E1, E2 and E3 enzymes. First, E1 enzyme activates the ubiquitin in an ATP-dependent way and transfers it to the ubiquitin-conjugating enzyme, E2. Finally, the ubiquitin ligase E3 catalyzes an isopeptide bond between the ubiquitin molecule and a lysine on the protein substrate [3] [4] [5] . After this mono-ubiquitination, the ubiquitin moiety itself can be ubiquitinated on eight amino groups: on the ε-amino groups of its seven K residues (K6, K11, K27, K29, K33, K48 and K63) and on the α-amino group of its N-terminal methionine. Various poly-ubiquitin chains can thereby be formed and are decisive for the targeted protein's fate. The best known poly-ubiquitinations are K48-linked chains, that trigger protein degradation by the 26S proteasome, and K63-linked chains, that control endocytosis, cellular trafficking and protein activity ( Figure 1 ) [2, [6] [7] [8] . The 26S proteasome is a large protein complex with a barrel shape that consists of a catalytic central core (20S) and two 19S regulatory caps at both ends of the core. The 20S core is made of two inner rings of seven β subunits and two outer rings with seven α subunits. The two 19S bind to the 20S and activate it in an ATP-dependent manner, thus allowing the targeted protein to enter the cavity to be proteolyzed into small peptides [9] .

Ubiquitinated proteins are subsequently recognized by other proteins or enzymes containing ubiquitin-binding domains, among which are de-ubiquitinase enzymes (DUBs). DUBs are able to hydrolyze isopeptide bonds formed between ubiquitin and the protein substrate or between ubiquitin moieties, with substrate and linkage specificity [10, 11] . This allows the recycling of ubiquitin molecules in the cell and other crucial cellular

ISGylation of cellular or viral proteins is also a post-translational modification, induced by type I IFNs stimulation in infected cells [35] . The interferon stimulated gene 15 protein (ISG15) is the first ubiquitin-like protein described in the literature [36, 37] . This protein contains two ubiquitin-like domains separated by a linker region [38] . Some studies indicate that ISG15 can be secreted similarly to a soluble cytokine from epithelial cells and lymphocytes to stimulate inflammatory response and IFNγ (type II IFNs) release [39] [40] [41] . As an ISG protein, ISG15 expression is induced by innate immune responses through type I IFN stimulation [42] , but also by other factors [43] [44] [45] . Similarly, ISG15 E1 (Ube1L/Uba7) [46] , E2 (Ube2L6) [47, 48] and E3 (Herc5) enzymes are induced by type I IFN expression [49] [50] [51] , as well as its main DUB (USP18) [52] . Herc5 is associated with ribosomes, leading to random and large ISGylations during protein translation. Therefore, several substrates can be ISGylated, even though oligomeric viral structure proteins are mainly targeted by ISG15 to be inactivated [53] .

Conjugation of neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8) to K residues of a protein substrate involves NEDD8-activating enzyme E1 (NAE), NEDD8-conjugating enzyme E2 (Ube2M and Ube2F) and different substratespecific E3 enzymes (reviewed in [54] ). The best characterized substrates of NEDD8 are cullin proteins, components of CRLs. Upon cullin NEDDylation, CRL undergoes conformational change which facilitates ubiquitin transfer from E2 enzyme to the substrate [55] . NEDDylation can be reversed by de-NEDDylase enzymes such as COP9 signalosome (CSN), which thus inactivates CRLs [56, 57] . More recently, non-cullin targets of NEDD8 were also highlighted, including the itchy-homolog (ITCH) [58] , Parkin [59] and MDM2 [60, 61] E3 ligases. NEDDylation of these other substrates seems to enhance their stability [62] .

Influenza A virus is a member of the Orthomyxoviridae family and consists of eight single-stranded negative sense RNA (ssRNA(−)) that encode 10 main proteins [63] . Hemagglutinin (HA) and neuraminidase (NA) are surface glycoproteins that facilitate viral entry and release, respectively. The M2 protein is an ion channel found in the virus envelope, itself surrounding a matrix formed by M1 protein oligomers. Each RNA segment is encapsidated by many nucleoprotein monomers (NP) and associated with an RNA-dependent RNA polymerase (PB1, PB2 and PA subunits), forming a viral ribonucleoprotein (vRNP) complex. The genome also encodes a nuclear export protein (NEP or NS2) and a nonstructural protein (NS1) [63] . More recently, other non-structural proteins produced from alternative splicing have been identified in infected cells (PB1-F2, PA-X, PA-N40) [64] . The IAV polymerase acts in two ways during the course of infection, as it first triggers viral RNA transcription for proteins expression, and then RNA replication for viral particles production through viral positive-sense complementary RNA (cRNA) production [65, 66] . Previous studies suggested that these two successive functions could be regulated by post-translational modifications of viral polymerase proteins such as PB1, PB2, PA and NP phosphorylation [67] and ubiquitination [68] or PB1 and NP SUMOylation [69, 70] .

As mentioned above, UPS has a crucial impact on the IAV life cycle. On the one hand, viral proteins ubiquitination mainly down-regulates their stability and function, but on the other hand, the lack of these modifications is clearly detrimental for proper infection [71] [72] [73] [74] [75] [76] [77] [78] . For instance, it was shown that 26S proteasome inhibition prevents IAV entry in the cell and negatively impacts viral polymerase activity [68, 74, 79] , while K48-linked poly-ubiquitination of viral proteins lead to their degradation [72, 75] . IAV is no exception, and a lot of viruses therefore evolved to counteract and exploit the UPS. For example, some viral proteins can target cellular proteins for K48-linked degradation or use cellular DUBs to protect themselves, as well as change cellular E3s' specificity or encode their own ubiquitin ligase enzymes [80] [81] [82] . Moreover, the UPS is particularly up-regulated in IAV-infected cells [83] .

The IAV life cycle follows different steps in which the UPS is involved, beginning with viral entry in host cell [26] . First, the viral particle binds to sialic acids on the host cell surface by its HA protein [84] . This binding leads to the virus' internalization in endosomes [63] , and the viral particle is acidified by M2 ion channel opening [85, 86] . Upon low pH, interactions between viral proteins weaken and HA undergoes a conformational change that triggers the fusion of the viral envelope with the endosome membrane [87] , leading to the release of the viral genome into the cytosol by M1 destabilization. At these steps, ITCH E3 ligase mediates ubiquitination and degradation of M1, facilitating vRNPs' release from endosomes [77] , and the cullin 3 (Cul3) E3 promotes endosome maturation and thus uncoating process [88, 89] .

Following this uncoating, vRNPs are then imported into the nucleus through importin α/β and are processed by the viral polymerase and host factors for transcription of viral mRNA and replication [90] [91] [92] . In the nucleus, the interaction between NP and RNA seems to be regulated by K184 residue mono-ubiquitination of NP. This modification is crucial for viral replication and is reversed by the cellular DUB USP11 [71, 73] . NP can also be poly-ubiquitinated on other K residues by other E3 ligases without targeting it for degradation. In fact, all viral polymerase proteins (PB1, PB2, PA and NP) are ubiquitinated and these modifications lead to enhanced polymerase activity and accumulation of viral RNA, cRNA and mRNA in the infected cell [68] . Besides ubiquitination, NP can also be SUMOylated at K7. This modification plays a crucial role in NP intracellular trafficking and therefore ensures its early nuclear retention for mature vRNPs' assembly. Notably, this SUMOylation is counteracted at the late stage of infection by host caspase-dependent cleavage [70] .

Meanwhile, viral proteins are produced in the cytoplasm and on the membrane of the endoplasmic reticulum, and are afterwards assembled into new virus particles with the newly synthetized vRNPs and the host plasma membrane-derived envelope, leading to the budding of new virions from the infected cell [63] . Aminoacyl-tRNA synthase complex-interacting multifunctional protein 2 (AIMP2) is a cellular protein that promotes vRNPs' nuclear export and replication at the late steps of infection. NEP protects this protein from K48-linked poly-ubiquitination by E3 ligases such as Parkin [93, 94] . In turn, AIMP2 inhibits K242 ubiquitination of M1 by ITCH and its subsequent degradation by the 26S proteasome [95] . At the late stages of infection, this K242 residue can therefore be SUMOylated, a crucial modification for vRNPs' nuclear export [96] .

In an infected cell, foreign and potentially pathogenic materials, namely pathogenassociated molecular patterns (PAMPs), are recognized by pattern recognition receptors (PRRs) localized on the cell and/or endosome membranes or in the cytoplasm. This recognition leads to type I (IFNα et IFNβ) and type III (IFNλ) IFNs as well as pro-inflammatory cytokines production through the activation of signaling pathways [97] . Subsequent paracrine and autocrine signals then establish an antiviral state in the infected cell and in surrounding cells through ISGs expression. Post-translational modifications such as ubiquitination and phosphorylation of several cellular factors regulate this signalization pathway [80, 98] . This regulation allows a duration and intensity balance in innate immune response [99] . In fact, excessive type I IFNs production leads to tissue injury and apoptosis induction [100, 101] .

Among innate immune response regulators, TRIM E3 ligases are key factors, leading to IRF3 and NF-κB activation [102] . A lot of TRIM proteins are known to inhibit IAV through different mechanisms [71, 72, [103] [104] [105] , and the best example described so far is TRIM25, as an IAV antagonist and innate immunity pathway activator ( Figure 2 ) [106, 107] . To ensure an immunity balance, TRIM25 itself can either be K48-linked poly-ubiquitinated to be discarded or de-ubiquitinated by ubiquitin specific protease 15 (USP15) to be stabilized [108] . TRIM proteins possess a conserved architecture consisting of a N-terminal RING domain, followed by one or two B-box domain(s), and a coiled-coil domain (CCD) involved in TRIM dimerization [109] [110] [111] and in interactions with several proteins [112] [113] [114] [115] [116] [117] . TRIMs' C-terminal region is characterized by non-catalytic domains responsible for substrate or other proteins recognition and for subcellular localization [116, 118] . Notably, this region possesses a PRY-SPRY domain in half of the TRIM proteins [118] .

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are cytoplasmic PRRs consisting of three described members: RIG-I, melanoma differentiation-associated protein 5 (MDA5) and LGP2. The first and best characterized RLR is RIG-I, which is particularly active during IAV infection and therefore the key sensor in these infected cells [119] [120] [121] . RIG-I possesses two N-terminally located caspase activation and recruitment domains (CARDs), followed by a central DExD/H-box helicase-like domain with ATPase and translocase activities, a linker (Br) and a C-terminal regulatory/repressor domain (CTR/RD) in its C-terminal region ( Figure 3 ). RIG-I principally detects short 5 -triphosphorylated double-stranded (ds)RNAs (5 -ppp dsRNAs) such as those produced in 5 and 3 UTR ends of IAV genome that are hybridized in a panhandle structure [97, [121] [122] [123] [124] [125] . Therefore, RIG-I senses IAV genomic RNAs associated with NP when they are imported into the nucleus or when they are incorporated into new virion particles at late stages of infection [125] [126] [127] . The Toll-like receptor 3 (TLR3), a membrane PRR, seems to be also involved in this IAV sensing [128] .

In the cytosol of non-infected cells, RIG-I is in an inactive state where its helicase domain binds its CARDs, hiding them from interactions and modifications [125, 129, 130] . Upon the sensing of a 5 -ppp dsRNA by CTR/RD, RIG-I undergoes conformational changes mediated by ATP hydrolysis [131] [132] [133] . CARDs become exposed and RIG-I is K63-linked poly-ubiquitinated at K172 residue by TRIM25 [106] and at K849 and K851 residues by the E3 Riplet [134] [135] [136] [137] [138] , respectively, even though recent studies suggest that RIG-I polyubiquitination mainly relies on Riplet activity ( Figure 3 ) [138] . Cadena et al. showed that Riplet plays both ubiquitin-dependent and independent roles in RIG-I activation, depending on dsRNAs' length. It mediates RIG-I poly-ubiquitination upon the recognition of short dsRNAs and induces RIG-I aggregate formation on longer dsRNAs, therefore amplifying RIG-I signaling [138] . also activates RIG-I through inhibition of its K48-linked poly-ubiquitination. In turn, RIG-I activates the NLRP3 inflammasome, that stimulates caspase-1 activation. Caspase-1 then mediates the maturation of interleukins IL-1β and IL-18, which are then secreted to promote inflammatory response. After its activation, RIG-I mainly binds to MAVS and promotes its multimerization at the mitochondrial membrane. Through signaling cascades not depicted here, MAVS mediates the recruitment of TBK1 and IKK kinases, which phosphorylate IRF3 and IRF7 transcription factors, and the NF-κB inhibitor IκB, respectively. IκB is then poly-ubiquitinated and degraded by the 26S proteasome. Activated IRF3 and IRF7, as well as activated NF-κB then translocate into the nucleus to promote type I IFNs (IFNα et IFNβ) expression, and proinflammatory cytokines, respectively. Notably, NF-κB also mediates IFNβ expression. ISGs activation (right): type I IFNs are then secreted in an autocrine and a paracrine way and bind to IFNAR1/2 heterodimeric receptor. Upon IFN binding, JAK1 and TYK2 kinases are activated and mediate phosphorylation of STAT1 and STAT2 transcription factors. These proteins then translocate into the nucleus with IRF9 and bind to ISRE sequences in ISG promoters to induce their transcription. Several ISGs are known to particularly counteract IAV replication (examples in the orange box). In turn, the NS1 protein hijacks innate immune response by targeting different proteins (bold black arrows), and notably ubiquitin factors (green).

Produced IFNs are secreted in an autocrine and a paracrine way from the infected cell and bind to IFNAR1/2 (type I IFNs) or IFNLR1 and IL10RB (type III IFNs) membrane The RLR sensor RIG-I is then activated by their presence and is K63 poly-ubiquitinated by Riplet and by TRIM25. The DUB OTUB1 also activates RIG-I through inhibition of its K48-linked poly-ubiquitination. In turn, RIG-I activates the NLRP3 inflammasome, that stimulates caspase-1 activation. Caspase-1 then mediates the maturation of interleukins IL-1β and IL-18, which are then secreted to promote inflammatory response. After its activation, RIG-I mainly binds to MAVS and promotes its multimerization at the mitochondrial membrane. Through signaling cascades not depicted here, MAVS mediates the recruitment of TBK1 and IKK kinases, which phosphorylate IRF3 and IRF7 transcription factors, and the NF-κB inhibitor IκB, respectively. IκB is then poly-ubiquitinated and degraded by the 26S proteasome. Activated IRF3 and IRF7, as well as activated NF-κB then translocate into the nucleus to promote type I IFNs (IFNα et IFNβ) expression, and pro-inflammatory cytokines, respectively. Notably, NF-κB also mediates IFNβ expression. ISGs activation (right): type I IFNs are then secreted in an autocrine and a paracrine way and bind to IFNAR1/2 heterodimeric receptor. Upon IFN binding, JAK1 and TYK2 kinases are activated and mediate phosphorylation of STAT1 and STAT2 transcription factors. These proteins then translocate into the nucleus with IRF9 and bind to ISRE sequences in ISG promoters to induce their transcription. Several ISGs are known to particularly counteract IAV replication (examples in the orange box). In turn, the NS1 protein hijacks innate immune response by targeting different proteins (bold black arrows), and notably ubiquitin factors (green). TRIM25 catalytic activity requires its own RING domain dimerization [139] , thus allowing TRIM25 PRY-SPRY domain to recognize the first RIG-I CARD and mediate the polyubiquitination at K172 on the second one ( Figure 3 ) [106, 140] . With less efficiency, RIG-I could also be activated by free K63 chains of ubiquitins synthetized by TRIM25 [14, 141] , and some studies suggest that these chains coil around CARDs and are then used as a scaffold for the next step [14, 141, 142] .

RIG-I poly-ubiquitination leads to its tetramerization and TRIM25 release [14, 133, 143, 144] . RIG-I then accumulates around mitochondria, where it binds to the mitochondrial antiviral signaling protein (MAVS) by its CARDs, leading to MAVS multimerization in filamentous structures [76, [145] [146] [147] [148] . MAVS mitochondrial localization is a determinant for innate immune response [149] , and the MAVS C-terminal transmembrane domain allows its anchor into the mitochondrial membrane, where it aggregates upon RIG-I activation [146, 150] . Through signaling cascades notably involving TAK1 and TRAFs proteins, MAVS multimerization leads to TBK1 and IKK kinases' recruitment. In turn, TBK1 phosphorylates and activates IRF3 and IRF7 transcription factors that direct type I and type III IFNs expression, while IKK kinases mediate phosphorylation of NF-κB inhibitor IκB [14, 97, 108, 145, 146, [151] [152] [153] [154] [155] [156] . Once phosphorylated, IκB is targeted by the SCF β-TrCP E3 ligase complex for proteasomal degradation, therefore activating NF-κB that translocates into the nucleus to direct pro-inflammatory cytokines as well as IFNβ expression [157] [158] [159] . Notably, it was shown that TBK1 and IKK kinases' recruitment relies on K63 poly-ubiquitination mechanisms ( Figure 2 ) [160, 161] .

Produced IFNs are secreted in an autocrine and a paracrine way from the infected cell and bind to IFNAR1/2 (type I IFNs) or IFNLR1 and IL10RB (type III IFNs) membrane receptors. Type I and type III IFNs are induced by the same PRRs and trigger similar downstream signaling, but recent studies suggest that type III IFNs' response is the primary defense in epithelial cells, while type I IFNs' machinery is more systemic and forms the second line of defense in case of broader infection [162] . Moreover, type III IFNs seem to trigger less inflammation than type I IFNs, thereby protecting epithelial tissue from immunopathology [163] . The binding of IFNs to their receptors activates signaling cascades that establish an antiviral state through phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2 transcription factors by Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) [164, 165] . These activated factors then associate with IRF9 to form an ISG factor 3 (ISGF3) complex that translocates into the nucleus where it binds to IFN-stimulated response element (ISRE) sequences in ISG promoters to induce their transcription ( Figure 2 ) [164, 166] .

Many ISGs particularly inhibit IAV replication, including myxovirus resistance (MxA), IFN-induced transmembrane (IFITM), 2 -5 oligoadenylate synthetase (OAS) and ribonuclease L (RNAseL) from OAS-RNase L pathway, protein kinase R (PKR), and ISG20 [97, [167] [168] [169] . Human cytosolic protein MxA is a guanylate-binding protein (GBP) that inhibits IAV by targeting viral transcription and by binding to the NP protein [170] [171] [172] . The IFITM protein family contains three members (IFITM1, IFITM2 and IFITM3) that have antiviral activities by blocking the fusion of the viral particle with cellular host membrane at the uncoating step [169, [173] [174] [175] . IFITM3 is notably down-regulated by its ubiquitination triggered by NEDD4 E3 ligase. In the absence of this E3 enzyme, cells are more resistant to IAV infection [76, 77] . dsRNAs activate OAS and lead to the production of poly(A) chains that in turn bind to and activate RNAseL [176] . This ribonuclease then cleaves viral RNA and therefore inhibits viral replication in infected cells [177] . Moreover, products from viral RNA degradation can activate RIG-I, therefore amplifying IFN response [124, 178] . The presence of dsRNAs in infected cells also activates the multifunctional PKR protein, which, for instance, phosphorylates the α subunit of the eukaryotic initiation factor 2 (eIF2α), subsequently inhibiting cellular but also viral proteins translation [179] . PKR also phosphorylates the NF-κB inhibitor IκB, and activates IRF3, leading to these transcription factors' activation [180, 181] . In addition, PKR stabilizes type I IFNs mRNA, thus enhancing IFNs production [182] . Finally, ISG20 is a 3 -5 exonuclease known to inhibit several ssRNA viruses. During IAV infection, ISG20 binds to NP to block virus replication and transcription [168] .

In response to PAMPs, RIG-I also activates inflammasomes, multiproteic complexes consisting of nucleotide oligomerization domain (NOD)-like receptor family member LRRand pyrin domain containing-3 (NLRP3), apoptosis-associated speck-like containing a caspase-recruitment domain (ASC) and pro-caspase-1 proteins [183, 184] . Inflammasomes are involved in the defense against several viruses of IAV [183, [185] [186] [187] . Indeed, NLRP3 is notably expressed in human bronchial epithelial cells [188] . Inflammasomes' activation also relies on PAMP detection by NLRP3 and on PKR activity [189] , as well as on protein flux through the M2 ion channel in the trans-Golgi network [190] and on IAV PB1-F2's presence in the cell [191] . Inflammasomes stimulate caspase-1 activation, which in turn cleaves inactive pro-interleukin (IL)-1β and pro-IL-18 into mature IL-1β and IL-18 forms, respectively, which are then secreted to stimulate inflammatory response ( Figure 2 ) [97, 183, 192] .

Autophagy, a self-eating mechanism, is involved in several cellular processes such as cell death or protein and organelle elimination through lysosomes, but it also plays a crucial part in innate immune response through TLRs activation, in inflammatory disorders, and in tumor suppression [193] [194] [195] . Depending on the host and on the virus strain, autophagy can further be used as a replication and pathogenesis enhancer [72, [194] [195] [196] [197] [198] or is subverted by viral proteins such as IAV M2 to enhance virion stability [199, 200] . Another cellular defense pathway triggered in response to intracellular pathogens is apoptosis, which is also involved in cell growth control [201] . This programmed cell death is notably hijacked by IAV to facilitate its replication [202] . Autophagy and apoptosis are both regulated by PKR signaling pathway [203, 204] .

In addition to TRIM25 and Riplet, other UPS and UPS-like factors are involved in the antiviral pathway during IAV infection, either by directly and indirectly targeting viral proteins or by amplifying immune response.

TRIM and DUB proteins are notable key players in antiviral responses against IAV infection. Among TRIMs, TRIM5, TRIM14, TRIM22, TRIM32 and TRIM41 directly target viral proteins to restrain replication [105, 116] . TRIM14 and TRIM41 bind to NP, leading to its ubiquitination and degradation, thus inhibiting vRNPs' formation and viral RNA replication [205, 206] . TRIM22 also interacts with NP to promote its K48-linked poly-ubiquitination and subsequent proteasomal degradation [71] . Nonetheless, it seems that some H1N1 strains evolved to evade TRIM22-mediated antiviral activity [207] . PB1 is targeted by TRIM32, which leads to a consecutive viral polymerase activity decrease [72] . Moreover, TRIM32 ligase activity stimulates the unc-51-like autophagy activating kinase 1 (ULK1), which controls autophagy induction through the formation of Beclin 1 complexes [208] . Several other TRIMs are implied in autophagy-associated antiviral mechanisms as well as in IAV-induced autophagy (reviewed in [105] ). Another TRIM, TRIM44, stabilizes MAVS by inhibiting its proteasomal degradation, therefore stabilizing and enhancing the IFN response [209] , while the TRIM28 protein is involved in pro-inflammatory cytokines production [210] .

Among DUBs regulating the RIG-I dependent innate immune response, USP21 is able to remove RIG-I K63-linked poly-ubiquitin chains [211] , USP4 hydrolyses RIG-I K48-linked chains [212] , and OTU domain-containing protein 1 (OTUD1) stabilizes a not yet identified E3 ligase, thus facilitating MAVS degradation [213] . Interestingly, Otubain-1 DUB (OTUB1) was recently described as an antiviral key regulator in IAV-infected cells. Upon infection, OTUB1 is induced by type I IFNs and is associated with RIG-I at the mitochondrial membranes, where it activates RIG-I by a double mechanism [214] . First, OTUB1 specifically hydrolyses RIG-I K48-linked chains, and then it inhibits these RIG-I K48-linked poly-ubiquitinations through the formation of an E2-repressive complex [214] [215] [216] .

Inflammasome complexes are also regulated by E3 and DUB enzymes. Indeed, the linear ubiquitin chain assembly complex (LUBAC) and TRIM33 E3 ligases promote inflammasomes' formation [217, 218] , while breast cancer 1 (BRCA1)/breast cancer 2 (BRCA2)containing complex subunit 3 (BRCC3) de-ubiquitinates NLRP3 [219] .

Other mechanisms, such as SUMOylation, ISGylation and NEDDylation, also regulate several viruses, such as IAV [220] [221] [222] . SUMOylated TRIM28 acts with other proteins to inhibit endogenous retroviral (ERV) elements' expression [223] [224] [225] [226] [227] [228] . Cellular ERVs can be recognized by RIG-I and/or MDA5, therefore leading to aberrant IFN stimulation [229] [230] [231] [232] [233] [234] . In IAV-infected cells, Schmidt et al. observed a diminution of SUMOylated TRIM28 levels, thus preparing cells for antiviral state establishment [220] . It was also shown that ISG15 conjugation, even at a low level, has a negative impact on the ability of the virus to replicate [235, 236] . In addition, MDM2 E3 ligase seems to enhance M1 and PB2 NEDDylation, leading to the destabilization of these viral proteins and the inhibition of IAV replication in vitro and in vivo [222, 237] . On the contrary, Sun et al. observed that IAV infection leads to the activation of NEDDylation pathway, which promotes virus growth but also pathogenicity. Indeed, cullin 1 NEDDylation can activate the NF-κB pathway and lead to the over-expression of pro-inflammatory cytokines that enhance viral pathogenicity [238] . NEDDylation modifications therefore seem to play a balancing role in the regulation of IAV replication.

Finally, the UPS is also indirectly involved in defense against IAV, through enhancement of proteasomal-mediated degradation of viral proteins. For example, Cyclophilin A accelerates the degradation of M1 [239] , while the long isoform of zinc finger antiviral protein (ZAP-L) associates with PA and PB2 to promote their presumably K48-linked poly-ubiquitination, although ZAP-L activity is counteracted by PB1 protein [75] .

As a response to antiviral state triggered by infected cells, many viruses evolved to counteract RIG-I-mediated innate immune response [240, 241] . For instance, IAV PB1-F2 and PB2 proteins interact with MAVS, NP prevents PKR-mediated IRF3 phosphorylation by binding to HSP40, and HA expression leads to IFNAR1 ubiquitination and degradation, thus inhibiting type I IFN production and response pathways [242] [243] [244] [245] . Accordingly, IAV can use the UPS not only to facilitate its replication, but also to evade the host's immune system.

Hence, different examples of UPS hijacking by IAV are described in the literature. Among others, the ubiquitination of M2 on its K78 residue regulates IAV replication by coordinating apoptosis and autophagy, two mechanisms used by the virus to spread and to control infection-mediated cellular death, even though the involved E3 ligase is still unknown [246] . Regardless of these significant examples, the main IAV virulence protein remains NS1, acting by direct interactions with proteins such as TRIM25 or indirect interactions by regulating host gene expression [107, [247] [248] [249] [250] [251] [252] [253] [254] [255] .

The RNA segment 8 of the IAV genome encodes for a mRNA, from which is synthetized the non-structural protein NS1. An alternative splicing of this mRNA results in the production of the NEP protein, which represents 10-15% of the segment 8 transcripts [256, 257] . A third transcript with a punctual mutation and a subsequently alternative splicing is also found in some viral strains, therefore expressing a NS3 protein with the same terminal ends as NS1 [258] . NS1 is generally a 230 amino acid (AAs) protein, even though its length may vary due to mutations depleting the stop codon at position 231 or creating a premature stop codon. For example, human IAV NS1 displayed 237 AAs from the late 1940s to the middle of the 1980s, while NS1 from the 2009 pandemic H1N1 strain only harbors 219 AAs [252, 259, 260] .

NS1 possesses an RNA-binding domain (RBD) in N-terminus (AAs 1-73), separated by a flexible linker region from an effector domain (ED) (AAs 85-207), which is followed by a C-terminal tail. The RBD forms three α-helices that are crucial for NS1 dimerization and for interaction with dsRNA [261] [262] [263] . Amino acids at position 38 and 41 are important for this binding function [263, 264] , while dimerization allows NS1 homodimer and then oligomer formation in infected cells [265] [266] [267] [268] . The RBD also displays a nuclear localization signal (NLS) from AA 35 to 41 [269, 270] . The ED contains a β-sheet structure and a long central helix as well as a nuclear export signal (NES) (AAs [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] . Together with NLS, this signal allows NS1 to shuttle from the nucleus to the cytoplasm during infection [271] . Interestingly, several cellular proteins have been shown to interact with NS1 ED [272] . Similarly to the linker region (10 to 15 AAs long), the C-terminal tail varies in length (11 to 33 AAs long), and it may contain, depending on the viral strain, a PDZ-binding motif involved in viral pathogenesis [273, 274] . Notably, H1N1 1918 NS1 contains a SUMOylation consensus site embedded in the PDZ-binding domain [275] . Most of the IAV strains also display a NLS in the tail domain (AAs 216-221) (Figure 3 ) [269] .

NS1 is known to inhibit the antiviral response in the host cell by means of a wide range of mechanisms, including through protein interactions, host shutoff and ubiquitination perturbations (reviewed in [252, 272, 276] ), turning NS1 into a key protein for viral replication cycle. Some studies therefore suggest that IFNβ-competent cells infected with IAV lacking NS1 considerably impair viral replication [277, 278] , as well as cells infected with IAV expressing a truncated form, low level or functional mutations of NS1 [279] [280] [281] [282] . Non-canonical antiviral pathways seem to be also targeted by NS1. Indeed, Schmidt et al. showed that NS1 can bind to ERV dsRNA and then inhibits the subsequent innate immune response [220] .

During the battle between IAV infection and innate immune response, NS1 inhibits IFN activation through the interaction with proteins such as Riplet [283] and IRF3 [247] . Moreover, it was shown that the NS1 ED of some IAV strains suppresses TRAF3 K63-linked poly-ubiquitination, probably through DUBs recruitment. This leads to the disruption of the MAVS and TRAF3 complex and to the impairment of subsequent IRF3 phosphorylation [284] . NS1 also inhibits NF-κB activation by blocking the β subunit of IKK [285] . Its RBD seems to play a crucial role in cytokine production and in cytokine sensitivity [286] .

In addition, NS1 was shown to regulate the expression of some JAK/STAT signaling inhibitors by binding to the DNA methyltransferase 3B (DNMT3B). Upon IAV infection, NS1 dissociates DNMT3B from gene promoters and changes its localization to the cytosol, where it is K48-linked poly-ubiquitinated and degraded, therefore leading to an enhanced expression of JAK/STAT signaling inhibitors [287] . NS1 also inhibits some specific ISGs, such as IFITM3, the expression of which is attenuated by NS1-mediated eIF4B degradation [272] . By binding viral RNA, NS1 competes with cellular RNA, binding proteins such as OAS, RNAse L, PKR and RIG-I, thus protecting them from degradation and inhibiting antiviral response (Figure 2 ) [251, [288] [289] [290] .

NS1 antagonizes inflammasome by a direct interaction with NLRP3, which prevents ASC ubiquitination and inflammasome activation ( Figure 2) [185, 291, 292] .

Finally, NS1 up-regulates the phosphoinositide-3-kinase (PI3K) pathway through direct interaction with the regulating subunit p85β of PI3K, causing downstream phosphorylation of the protein kinase B (Akt) [293] [294] [295] [296] . Notably, p85β possesses a CCD to which NS1 ED binds [297, 298] . This leads to an increase in the viral internalization rate, apoptosis inhibition [299] , and an enhancement of IRF3 activity [300, 301] . While NS1 seems to inhibit apoptosis, recent studies suggest that it also has a pro-apoptotic effect [302] . NS1 dual function in apoptosis regulation therefore may vary depending on the stage of viral infection. Indeed, induction of apoptosis seems to be essential for vRNPs' nuclear trafficking at the beginning of the infection, while the limitation of apoptosis at later stages could prevent premature viral particles release and death of infected cells [303] .

Another mechanism triggered by NS1 to impair the antiviral state in infected cells is host shutoff, i.e., inhibition of host genes expression. NS1 mainly inhibits cellular mRNAs processing by binding to CPSF30, a key component of pre-mRNA 3 -end formation machinery [260, 279, [304] [305] [306] [307] . This interaction prevents the recognition by CPSF30 of poly(A) signals at 3 -end of mRNAs during their transcription, thereby blocking immature mRNAs' cleavage and poly(A) tail addition [307, 308] . Poly(A) tail allows mRNAs' stabilization, nuclear export, and translation [308] . In its absence, immature mRNAs thus accumulate in the nucleus of infected cells, leading to a general host shutoff, affecting, among other things, the expression of IFNs, ISGs, and pro-inflammatory proteins [272, 306, 309] . In this way, NS1 also binds and inhibits PABPII, the nuclear poly(A)-binding protein II, which stimulates the synthesis of long poly(A) tails [309] . It was shown that NS1 RBD is able to bind host dsDNAs, therefore inhibiting the loading of transcriptional machinery to IAV antiviral genes [310] . Nuclear RNA export factor 1 (NFX1), ribonucleic acid export 1 (RAE1) and p15 are examples of mRNA export machinery proteins also targeted by NS1 from the H1N1 WSN strain [311] . Additionally, NS1 enhances viral mRNAs translation to the detriment of cellular mRNAs by recruiting eIF4GI to the viral mRNA 5 -UTR region [312] .

One of the main antiviral targets of NS1 is TRIM25 [107, 283] , therefore interfering with its E3 ligase activity and with IFN signaling pathway activation ( Figure 2 ) [107] . The interaction between PRY-SPRY domain of TRIM25 and its own CCD is essential to mediate RIG-I ubiquitination [118] , and NS1 directly competes with this binding [107, 118, 144] . Indeed, NS1 presumably binds to TRIM25 CCD via its functional ED amino acids 96 and 97 ( Figure 3 ) [107] . Interestingly, this interface is the same as the one in NS1 and p85β interaction, suggesting that NS1 uses the same ED surface to recognize similar structures in various targets [118, 297, 298] . NS1 and TRIM25 complex formation therefore inhibits the correct juxtaposition of TRIM25 PRY-SPRY and RING domains, and thus TRIM25 multimerization and activity [107, 118] . However, this binding does not impair free K63-linked poly-ubiquitin chains formation by TRIM25, neither the formation of TRIM25 and RIG-I complex in infected-cells cytoplasm [118] . On the contrary, NS1 also interacts with RIG-I and inhibits its activation by sequestrating its RNA helicase and its ligand [255, 313, 314] . Moreover, a recent study suggested that NS1 RBD from 1918 H1N1 strain directly binds to the RIG-I second CARD and inhibits its ubiquitination ( Figure 3 ) [315] , and that the R21Q natural mutation of some NS1 proteins intriguingly impairs this inhibition, leading to a stronger immune response [315, 316] . This mutation could therefore be a specific adaptation of some strains to host species [283, 315] . Indeed, it has been shown that H3N2 and H2N2 IAV strains infections lead to a high IRF3 and IFNβ activation, despite a proper interaction between NS1 and TRIM25 [317, 318] . Meyerson et al. thus suggested that NS1 inhibits another antiviral function of TRIM25, independent of its ligase activity and of RIG-I. In fact, TRIM25 can bind to vRNP RNA and proteins in infected-cell nucleus, preventing viral RNA elongation [196] . Finally, NS1 is also able to suppress TRIM25 expression at a transcriptional level through up-regulation of Dot1L methyltransferase during infection [319] . Viruses 2021, 13, x FOR PEER REVIEW 13 of 29 (3), leading to antiviral response activation. In turn, IAV NS1 protein can inhibit these two proteins (red arrows) (4). NS1 RBD from 1918 H1N1 strain directly binds to and inhibits poly-ubiquitination of RIG-I second CARD, while amino acids 96 and 97 in ED interact with TRIM25 CCD, therefore inhibiting TRIM25 dimerization.

NS1 inhibits the RIG-I pathway by up-regulating the expression of A20 DUB (other name TNFAIP3), a negative regulator of the innate immune response [99, 320, 321] . A20 suppresses the antiviral state established during infection [322] , and its up-regulation by NS1 seems to be proportional to strain virulence [99] . A20 is a dual-ubiquitin editing enzyme that contains a N-terminal DUB activity and seven Zn finger domains with E3 ligase activity in its C-terminal region, which regulate innate immune response [323, 324] . OTUB1 is also targeted by NS1, even though the mechanism is still undefined. NS1 could trigger OTUB1 proteasomal degradation at the later stages of infection, leading to the inhibition of IRF3 and NF-κB activation, and thus preventing the antiviral response (Figure 2) [214].

p53 is a well-known transcription factor and tumor suppressor that accumulates in the nucleus upon cellular stress [325, 326] . It regulates several biological processes, including apoptosis and antiviral mechanisms by regulating infected-cell fate [327] [328] [329] [330] [331] [332] . p53 activates, among other things, the transcription of its main negative regulator, MDM2, a RING E3 ligase that in turn binds to p53 and mediates its poly-ubiquitination and proteasomal degradation. MDM2 can also mediate p53 NEDDylation [60] . p53 stability is therefore dependent on its interaction with MDM2, as well as on the MDM2 level or cellular localization [295] .

IAV was shown to regulate p53 transcriptional activity, through its stabilization by NS1 [330, 333, 334] . This p53 stabilization in infected cells is associated with a defect of MDM2-mediated ubiquitination of p53 [335] . Pizzorno et al. showed that NS1 is (3), leading to antiviral response activation. In turn, IAV NS1 protein can inhibit these two proteins (red arrows) (4). NS1 RBD from 1918 H1N1 strain directly binds to and inhibits poly-ubiquitination of RIG-I second CARD, while amino acids 96 and 97 in ED interact with TRIM25 CCD, therefore inhibiting TRIM25 dimerization.

NS1 inhibits the RIG-I pathway by up-regulating the expression of A20 DUB (other name TNFAIP3), a negative regulator of the innate immune response [99, 320, 321] . A20 suppresses the antiviral state established during infection [322] , and its up-regulation by NS1 seems to be proportional to strain virulence [99] . A20 is a dual-ubiquitin editing enzyme that contains a N-terminal DUB activity and seven Zn finger domains with E3 ligase activity in its C-terminal region, which regulate innate immune response [323, 324] . OTUB1 is also targeted by NS1, even though the mechanism is still undefined. NS1 could trigger OTUB1 proteasomal degradation at the later stages of infection, leading to the inhibition of IRF3 and NF-κB activation, and thus preventing the antiviral response ( Figure 2) [214].

p53 is a well-known transcription factor and tumor suppressor that accumulates in the nucleus upon cellular stress [325, 326] . It regulates several biological processes, including apoptosis and antiviral mechanisms by regulating infected-cell fate [327] [328] [329] [330] [331] [332] . p53 activates, among other things, the transcription of its main negative regulator, MDM2, a RING E3 ligase that in turn binds to p53 and mediates its poly-ubiquitination and proteasomal degradation. MDM2 can also mediate p53 NEDDylation [60] . p53 stability is therefore dependent on its interaction with MDM2, as well as on the MDM2 level or cellular localization [295] .

IAV was shown to regulate p53 transcriptional activity, through its stabilization by NS1 [330, 333, 334] . This p53 stabilization in infected cells is associated with a defect of MDM2-mediated ubiquitination of p53 [335] . Pizzorno et al. showed that NS1 is responsible for proteasomal-mediated degradation of MDM2 at early stages of infection, and that it also modifies MDM2 subcellular localization during IAV infection [336] . As with p53, MDM2 could also plays an antiviral role, independently of its ligase activity and p53 [336] . According to the ambivalent role of apoptosis during IAV infection, MDM2 could be used by NS1 at early stages of infection to promote IAV propagation [303] . However, MDM2 is involved in many other pathways linked to IAV infection, such as cell cycle control or NF-κB signalization, perhaps ensuring antiviral effect by other mechanisms [337, 338] .

Similarly to NP discussed previously, NS1 also interacts with the cellular SUMOylation system during IAV infection. Indeed, some studies suggest that most of IAV strains possess a SUMOylated NS1 protein, and that different lysine residues can be targeted, even though K131 seems to be the main NS1 SUMOylation site. These studies also highlight the crucial, but not essential, role of NS1 SUMOylation in virus replication [339] [340] [341] . Santos et al. notably showed that SUMOylation at K70 and K219 has no impact on NS1 stability and localization but can affect NS1 oligomerization and therefore NS1 functions. Furthermore, they showed that a modification of NS1 SUMOylation level negatively impacts the ability of NS1 to counteract IFN response [340] .

Moreover, SUMOylation of NS1 was recently shown to take part in host shutoff by enhancing NS1 association with nuclear ribonucleoprotein complexes that control the activity of the RNA polymerase II [275] .

Interestingly, NS1 from influenza B (IBV) virus also antagonizes the RIG-I-mediated antiviral response [342] . Notably, IBV NS1 binds to the N-terminal ubiquitin-like domain and to the linker region of ISG15 [46, 343, 344] , inhibiting its activity and its secretion [39] . Moreover, IBV NS1 binds and sequesters ISGylated proteins, such as NP, to prevent its undesirable and premature inclusion into vRNPs [235, 343] .

The ubiquitin-proteasome system, as well as ubiquitin-like machineries, are key cellular processes involved in various pathways, including notably innate immune response. Upon influenza A virus infection, ubiquitination-mediated RIG-I activation leads to an antiviral state establishment in infected and surrounding cells, thus inhibiting IAV replication through IFNs, ISGs and pro-inflammatory cytokines expression. Several UPS factors are described to enhance and stabilize this innate immune response and to directly target IAV proteins for their proteasomal-mediated degradation. In turn, IAV evolved to hijack the UPS and use it to enter the cell and spread, disrupting UPS activity from antiviral to proviral roles. Furthermore, the viral non-structural protein NS1, a well-known virulence factor, developed many mechanisms to antagonize innate immunity, from direct interactions with cellular proteins to the general inhibition of host gene expression. Interestingly, NS1 specifically targets UPS factors such as TRIM25, A20, OTUB1 and MDM2, SUMOylation system, as well as ISG15 in the case of influenza B virus. NS1 activity seems to vary depending on the infection timing, and further investigations are therefore needed to decipher the role of NS1 in ubiquitin perturbations during the course of IAV infection. We are currently investigating the identification of UPS factors interacting with IAV NS1 and the functional characterization of some of them.

Ubiquitin Linkages Make a Difference

Nonproteolytic Functions of Ubiquitin in Cell Signaling

A Multiubiquitin Chain Is Confined to Specific Lysine in a Targeted Short-Lived Protein

The Unravelling of the Ubiquitin System

Components of Ubiquitin-Protein Ligase System. Resolution, Affinity Purification, and Role in Protein Breakdown

The Ubiquitin Code

Atypical Ubiquitylation-the Unexplored World of Polyubiquitin beyond Lys48 and Lys63 Linkages

The Ubiquitin Code and Its Decoding Machinery in the Endocytic Pathway

The Proteasome: Overview of Structure and Functions

Breaking the Chains: Structure and Function of the Deubiquitinases

Deubiquitylases from Genes to Organism

Ubiquitin Modifications

Proteasomes Activate Aggresome Disassembly and Clearance by Producing Unanchored Ubiquitin Chains

Reconstitution of the RIG-I Pathway Reveals a Signaling Role of Unanchored Polyubiquitin Chains in Innate Immunity

IUUCD 2.0: An Update with Rich Annotations for Ubiquitin and Ubiquitin-like Conjugations

New insights into ubiquitin E3 ligase mechanism

Ubiquitin ligases: Structure, function, and regulation

RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination

Regulating the Human HECT E3 Ligases

HECT and RING finger families of E3 ubiquitin ligases at a glance

The HECT Family of E3 Ubiquitin Ligases: Multiple Players in Cancer Development

Cullin-RING Ubiquitin Ligases: Global Regulation and Activation Cycles

TRIM family proteins: Roles in autophagy, immunity, and carcinogenesis

Types of Ubiquitin Ligases

Influenza A virus-host protein interactions control viral pathogenesis

Ubiquitin in influenza virus entry and innate immunity

Ubiquitin-like Protein Conjugation and the Ubiquitin-Proteasome System as Drug Targets

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Sumo and the Cellular Stress Response

Interplay between Viruses and Host Sumoylation Pathways

Innate Immunity to RNA Virus Is Regulated by Temporal and Reversible Sumoylation of RIG-I and MDA5

Sumoylation Promotes the Stability of the DNA Sensor CGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus

SUMO2 and SUMO3 Redundantly Prevent a Noncanonical Type I Interferon Response

Sumoylation Coordinates the Repression of Inflammatory and Anti-Viral Gene-Expression Programs during Innate Sensing

Human ISG15 Conjugation Targets Both IFN-Induced and Constitutively Expressed Proteins Functioning in Diverse Cellular Pathways

Interferon Induces a 15-Kilodalton Protein Exhibiting Marked Homology to Ubiquitin

The Interferon-Inducible 15-KDa Ubiquitin Homolog Conjugates to Intracellular Proteins

Crystal Structure of the Interferon-Induced Ubiquitin-like Protein ISG15

Modulation of Extracellular ISG15 Signaling by Pathogens and Viral Effector Proteins

In Vitro and in Vivo Secretion of Human ISG15, an IFN-Induced Immunomodulatory Cytokine

A Human 15-KDa IFN-Induced Protein Induces the Secretion of IFN-Gamma

Accumulation of an MRNA and Protein in Interferon-Treated Ehrlich Ascites Tumour Cells

Interferon-Independent Upregulation of Interferon-Stimulated Genes during Human Cytomegalovirus Infection Is Dependent on IRF3 Expression

Up-Regulation of Interferon-Stimulated Gene 15 and Its Conjugation Machinery, UbE1L and UbcH8 Expression by Tumor Necrosis Factor-α through P38 MAPK and JNK Signaling Pathways in Human Lung Carcinoma

Influenza B Virus NS1 Protein Inhibits Conjugation of the Interferon (IFN)-Induced Ubiquitin-like ISG15 Protein

Interferon-Inducible Ubiquitin E2, Ubc8, Is a Conjugating Enzyme for Protein ISGylation

The UbcH8 Ubiquitin E2 Enzyme Is Also the E2 Enzyme for ISG15, an IFN-α/β-Induced Ubiquitin-like Protein

Herc5, an Interferon-Induced HECT E3 Enzyme, Is Required for Conjugation of ISG15 in Human Cells

HERC6 Is the Main E3 Ligase for Global ISG15 Conjugation in Mouse Cells

MHERC6 Is the Essential ISG15 E3 Ligase in the Murine System

UBP43 (USP18) Specifically Removes ISG15 from Conjugated Proteins

The ISG15 Conjugation System Broadly Targets Newly Synthesized Proteins: Implications for the Antiviral Function of ISG15

Protein Neddylation: Beyond Cullin-RING Ligases

Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation

The COP9 Signalosome: A Multi-DUB Complex

Set Them Free: F-Box Protein Exchange by Cand1

Itch Promotes the Neddylation of JunB and Regulates JunB-Dependent Transcription

Neddylation Positively Regulates the Ubiquitin E3 Ligase Activity of Parkin

Mdm2-Mediated NEDD8 Conjugation of P53 Inhibits Its Transcriptional Activity

Src Phosphorylation Converts Mdm2 from a Ubiquitinating to a Neddylating E3 Ligase

Diverse and Pivotal Roles of Neddylation in Metabolism and Immunity

Molecular Mechanisms Enhancing the Proteome of Influenza A Viruses: An Overview of Recently Discovered Proteins

A single amino acid in the PB2 gene of influenza A virus is a determinant of host range

NS2/NEP Protein Regulates Transcription and Replication of the Influenza Virus RNA Genome

Mapping the Phosphoproteome of Influenza A and B Viruses by Mass Spectrometry

Ubiquitination upregulates influenza virus polymerase function

Influenza A Virus Interacts Extensively with the Cellular SUMOylation System during Infection

Sumoylation of Influenza A Virus Nucleoprotein Is Essential for Intracellular Trafficking and Virus Growth

TRIM22 Inhibits Influenza A Virus Infection by Targeting the Viral Nucleoprotein for Degradation

TRIM32 senses and restricts influenza A virus by ubiquitination of PB1 polymerase

Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication

Inhibition of the Ubiquitin-Proteasome System Affects Influenza A Virus Infection at a Postfusion Step

Battle between Influenza A Virus and a Newly Identified Antiviral Activity of the PARP-Containing ZAPL Protein

Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3

Pooled RNAi Screen Identifies Ubiquitin Ligase Itch as Crucial for Influenza A Virus Release from the Endosome during Virus Entry

Cellular networks involved in the influenza virus life cycle

The Ubiquitin-Vacuolar Protein Sorting System Is Selectively Required during Entry of Influenza Virus into Host Cells

The Ubiquitin-Conjugating System: Multiple Roles in Viral Replication and Infection

Viral mimicry to usurp ubiquitin and sumo host pathways

HSV-1 ICP0: Paving the Way for Viral Replication

Influenza A Infection of Primary Human Airway Epithelial Cells Up-Regulates Proteins Related to Purine Metabolism and Ubiquitin-Related Signaling

Sialic acid species as a determinant of the host range of influenza A viruses

Influenza virus M2 protein has ion channel activity

Stepwise priming by acidic pH and a high K+ concentration is required for efficient uncoating of influenza a virus cores after penetration

Membrane fusion activity of influenza virus

Cullin-3 Regulates Late Endosome Maturation

Cullin-3 and the endocytic system: New functions of ubiquitination for endosome maturation

An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein

At the centre: Influenza A virus ribonucleoproteins

Nuclear Import of Influenza A Viral Ribonucleoprotein Complexes Is Mediated by Two Nuclear Localization Sequences on Viral Nucleoprotein

Phosphorylation by the C-Abl Protein Tyrosine Kinase Inhibits Parkin's Ubiquitination and Protective Function

Parthanatos Mediates AIMP2 Activated Age Dependent Dopaminergic Neuronal Loss

Interaction of NS2 with AIMP2 Facilitates the Switch from Ubiquitination to SUMOylation of M1 in Influenza a Virus-Infected Cells

The SUMOylation of Matrix Protein M1 Modulates the Assembly and Morphogenesis of Influenza A Virus

Innate Immunity to Influenza Virus Infection

Ubiquitination in the Antiviral Immune Response

Influenza a Virus NS1 Protein Induced A20 Contributes to Viral Replication by Suppressing Interferon-Induced Antiviral Response

Pathogenic Potential of Interferon Aβ in Acute Influenza Infection

IFNλ Is a Potent Anti-influenza Therapeutic without the Inflammatory Side Effects of IFNα Treatment

Identification of a Genomic Reservoir for New TRIM Genes in Primate Genomes

Overlapping and Distinct Molecular Determinants Dictating the Antiviral Activities of TRIM56 against Flaviviruses and Coronavirus

The Roles of the TRIM E3-Ubiquitin Ligase Family in Innate Antiviral Immunity

TRIM Proteins and Their Roles in the Influenza Virus Life Cycle

TRIM25 RING-Finger E3 Ubiquitin Ligase Is Essential for RIG-I-Mediated Antiviral Activity

Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I

The Ubiquitin-Specific Protease USP15 Promotes RIG-I-Mediated Antiviral Signaling by Deubiquitylating TRIM25

Origin and diversification of TRIM ubiquitin ligases

Structural Determinants of TRIM Protein Function

The Tripartite Motif Family Identifies Cell Compartments

Crystal Structure of Cytomegalovirus IE1 Protein Reveals Targeting of TRIM Family Member PML via Coiled-Coil Interactions

The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML De Novo SUMOylation

Protein Complexes Comprise a Family of E3 Ubiquitin Ligases

Degradation of AMPK by a Cancer-Specific Ubiquitin Ligase

TRIM Proteins and Their Roles in Antiviral Host Defenses

TRIM Proteins in Cancer

Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

Structural Mechanism of RNA Recognition by the RIG-I-like Receptors

The RNA Helicase RIG-I Has an Essential Function in Double-Stranded RNA-Induced Innate Antiviral Responses

Preference of RIG-I for Short Viral RNA Molecules in Infected Cells Revealed by next-Generation Sequencing

Viral Tricks to Grid-Lock the Type I Interferon System

Standing on Three Legs: Antiviral Activities of RIG-I against Influenza Viruses

RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5 -Phosphates

RIG-I Detects Viral Genomic RNA during Negative-Strand RNA Virus Infection

Influenza Virus Adaptation PB2-627K Modulates Nucleocapsid Inhibition by the Pathogen Sensor RIG-I

RIG-I and TLR3 Are Both Required for Maximum Interferon Induction by Influenza Virus in Human Lung Alveolar Epithelial Cells

A Structure-Based Model of RIG-I Activation

Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5

ATPase-Driven Oligomerization of RIG-I on RNA Allows Optimal Activation of Type-I Interferon

Structure and Dynamics of the Second CARD of Human RIG-I Provide Mechanistic Insights into Regulation of RIG-I Activation

Structural Basis for the Activation of Innate Immune Pattern-Recognition Receptor RIG-I by Viral RNA

The ubiquitin ligase riplet is essential for RIG-Idependent innate immune responses to RNA virus infection

REUL Is a Novel E3 Ubiquitin Ligase and Stimulator of Retinoic-Acid-Inducible Gene-I

Riplet/RNF135, a RING Finger Protein, Ubiquitinates RIG-I to Promote Interferon-Beta Induction during the Early Phase of Viral Infection

A hierarchical mechanism of RIG-I ubiquitination provides sensitivity, robustness and synergy in antiviral immune responses

Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity

Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway

Crystal Structure of the TRIM25 B30.2 (PRYSPRY) Domain: A Key Component of Antiviral Signalling

Structural Basis for Ubiquitin-Mediated Antiviral Signal Activation by RIG-I

Regulation of RIG-I activation by K63-linked polyubiquitination

Structural Insights into the Activation of RIG-I, a Nanosensor for Viral RNAs

Subcellular Localizations of RIG-I, TRIM25, and MAVS Complexes

Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein That Activates NF-KB and IRF3

IPS-1, an Adaptor Triggering RIG-I-and Mda5-Mediated Type I Interferon Induction

Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I

Correction: Structural Basis for the Prion-like MAVS Filaments in Antiviral Innate Immunity

Hepatitis C Virus Protease NS3/4A Cleaves Mitochondrial Antiviral Signaling Protein off the Mitochondria to Evade Innate Immunity

MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response

VISA Is an Adapter Protein Required for Virus-Triggered IFN-Beta Signaling

Mechanisms of RIG-I-Like Receptor Activation and Manipulation by Viral Pathogens

Sensing of RNA Viruses: A Review of Innate Immune Receptors Involved in Recognizing RNA Virus Invasion

Innate Immunity to Virus Infection

Influenza Viruses Control the Vertebrate Type I Interferon System: Factors, Mechanisms, and Consequences

Interferon-λ in the Context of Viral Infections: Production, Response and Therapeutic Implications

SCFβ-TrCP Ubiquitin Ligase-Mediated Processing of NF-KB P105 Requires Phosphorylation of Its C-Terminus by IκB Kinase

Molecular Pathways in Virus-Induced Cytokine Production. Microbiol

Defining Emerging Roles for NF-KB in Antivirus Responses: Revisiting the Interferon-β Enhanceosome Paradigm

Ubiquitin-Mediated Activation of TAK1 and IKK

MAVS Activates TBK1 and IKKε through TRAFs in NEMO Dependent and Independent Manner

Interferon-Λs: Front-Line Guardians of Immunity and Homeostasis in the Respiratory Tract

Interferon-λ Mediates Non-Redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness

Induction and Function of Type I and III Interferon in Response to Viral Infection

From Interferons to Cytokines

Interferons and Viruses: An Evolutionary Arms Race of Molecular Interactions

Host Cell Restriction Factors That Limit Influenza A Infection

Influenza A Virus-Induced Expression of ISG20 Inhibits Viral Replication by Interacting with Nucleoprotein

IFITM3 Restricts Influenza A Virus Entry by Blocking the Formation of Fusion Pores Following Virus-Endosome Hemifusion

Nuclear MxA Proteins Form a Complex with Influenza Virus NP and Inhibit the Transcription of the Engineered Influenza Virus Genome

Enhanced Virus Resistance of Transgenic Mice Expressing the Human MxA Protein

Mx GTPases: Dynamin-like Antiviral Machines of Innate Immunity

IFITM3 Inhibits Influenza a Virus Infection by Preventing Cytosolic Entry

The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus, West Nile Virus, and Dengue Virus

IFITM-Family Proteins: The Cell's First Line of Antiviral Defense

Inhibition of Cell-Free Protein Synthesis by PppA2 P5 A2 P5 A: A Novel Oligonucleotide Synthesized by Interferon-Treated L Cell Extracts

Viral Phosphodiesterases That Antagonize Double-Stranded RNA Signaling to RNase L by Degrading 2-5A

Small Self-RNA Generated by RNase L Amplifies Antiviral Innate Immunity

Double-Stranded RNA-Dependent Protein Kinase Activates Transcription Factor NF-Kappa B by Phosphorylating I Kappa

Induction of Protein Kinase PKR-Dependent Activation of Interferon Regulatory Factor 3 by Vaccinia Virus Occurs through Adapter IPS-1 Signaling

Reis e Sousa, C. Protein Kinase R Contributes to Immunity against Specific Viruses by Regulating Interferon MRNA Integrity

Response of Host Inflammasomes to Viral Infection

Spotlight on the NLRP3 Inflammasome Pathway

The RNA-and TRIM25-Binding Domains of Influenza Virus NS1 Protein Are Essential for Suppression of NLRP3 Inflammasome-Mediated Interleukin-1β Secretion

RNA Viruses Promote Activation of the NLRP3 Inflammasome through a RIP1-RIP3-DRP1 Signaling Pathway

HCV Genomic RNA Activates the NLRP3 Inflammasome in Human Myeloid Cells

Type I IFN Triggers RIG-I/TLR3/NLRP3-Dependent Inflammasome Activation in Influenza A Virus Infected Cells

Novel Role of PKR in Inflammasome Activation and HMGB1 Release

Influenza Virus Activates Inflammasomes via Its Intracellular M2 Ion Channel

Activation of the NLRP3 Inflammasome by IAV Virulence Protein PB1-F2 Contributes to Severe Pathophysiology and Disease

Induction and Evasion of Type I Interferon Responses by Influenza Viruses

Autophagy: Renovation of Cells and Tissues

Biological Functions of Autophagy Genes: A Disease Perspective

Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation

The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis

Avian Influenza A Virus H5N1 Causes Autophagy-Mediated Cell Death through Suppression of MTOR Signaling

A LC3-Interacting Motif in the Influenza A Virus M2 Protein Is Required to Subvert Autophagy and Maintain Virion Stability

Matrix Protein 2 of Influenza A Virus Blocks Autophagosome Fusion with Lysosomes

Viral Control of Mitochondrial Apoptosis

Regulation of Starvationand Virus-Induced Autophagy by the EIF2alpha Kinase Signaling Pathway

The Role of Host EIF2α in Viral Infection

Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein-Protein Interaction with

Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection

Mutations Conferring Increased Sensitivity to Tripartite Motif 22 Restriction Accumulated Progressively in the Nucleoprotein of Seasonal Influenza A (H1N1) Viruses between

TRIM Proteins in Autophagy: Selective Sensors in Cell Damage and Innate Immune Responses

Novel Function of Trim44 Promotes an Antiviral Response by Stabilizing VISA

Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells

USP21 Negatively Regulates Antiviral Response by Acting as a RIG-I Deubiquitinase

USP4 Positively Regulates RIG-I-Mediated Antiviral Response through Deubiquitination and Stabilization of RIG-I

Induction of OTUD1 by RNA Viruses Potently Inhibits Innate Immune Responses by Promoting Degradation of the MAVS/TRAF3/TRAF6 Signalosome

OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1

OTUB1 Enhances TGFβ Signalling by Inhibiting the Ubiquitylation and Degradation of Active SMAD2/3

Positive Regulation of P53 Stability and Activity by the Deubiquitinating Enzyme Otubain 1

The Linear Ubiquitin Assembly Complex (LUBAC) Is Essential for NLRP3 Inflammasome Activation

The E3 Ubiquitin Ligase Tripartite Motif 33 Is Essential for Cytosolic RNA-Induced NLRP3 Inflammasome Activation

Deubiquitination of NLRP3 by BRCC3 Critically Regulates Inflammasome Activity

An Influenza Virus-Triggered SUMO Switch Orchestrates Co-Opted Endogenous Retroviruses to Stimulate Host Antiviral Immunity

The Antiviral Activities of ISG15

Neddylation of M1 Negatively Regulates the Replication of Influenza A Virus

KAP1 Controls Endogenous Retroviruses in Embryonic Stem Cells

Interplay of TRIM28 and DNA Methylation in Controlling Human Endogenous Retroelements

Proviral Silencing in Embryonic Stem Cells Requires the Histone Methyltransferase ESET

Targeting Histone Deacetylase Complexes via KRAB-Zinc Finger Proteins: The PHD and Bromodomains of KAP-1 Form a Cooperative Unit That Recruits a Novel Isoform of the Mi-2α Subunit of NuRD

PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Which Is Required for Gene Silencing

Sumoylation of the Transcriptional Intermediary Factor 1beta (TIF1beta), the Co-Repressor of the KRAB Multifinger Proteins, Is Required for Its Transcriptional Activity and Is Modulated by the KRAB Domain

DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts

Silencing of Retrotransposons by SETDB1 Inhibits the Interferon Response in Acute Myeloid Leukemia

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via DsRNA Including Endogenous Retroviruses

KAP1 Regulates Endogenous Retroviruses in Adult Human Cells and Contributes to Innate Immune Control

Vitamin C Increases Viral Mimicry Induced by 5-Aza-2 -Deoxycytidine

Influenza B Virus Non-Structural Protein 1 Counteracts ISG15 Antiviral Activity by Sequestering ISGylated Viral Proteins

Interferon-Induced ISG15 Conjugation Inhibits Influenza A Virus Gene Expression and Replication in Human Cells

NEDDylation of PB2 Reduces Its Stability and Blocks the Replication of Influenza A Virus

Inhibition of Neddylation Pathway Represses Influenza Virus Replication and Pro-Inflammatory Responses

Cyclophilin a Restricts Influenza a Virus Replication through Degradation of the M1 Protein

Strategies of Highly Pathogenic RNA Viruses to Block DsRNA Detection by RIG-I-like Receptors: Hide, Mask, Hit

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon by Binding to MAVS and Decreasing Mitochondrial Membrane Potential

The PB2 Subunit of the Influenza Virus RNA Polymerase Affects Virulence by Interacting with the Mitochondrial Antiviral Signaling Protein and Inhibiting Expression of Beta Interferon

Influenza A Virus Nucleoprotein Exploits Hsp40 to Inhibit PKR Activation

Hemagglutinin of influenza A virus antagonizes type I interferon (IFN) responses by inducing degradation of type I IFN receptor 1

Ubiquitination of the Cytoplasmic Domain of Influenza A Virus M2 Protein Is Crucial for Production of Infectious Virus Particles

Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza a Virus NS1

The NS1 Protein of Influenza A Virus Blocks RIG-I-Mediated Activation of the Noncanonical NF-KB Pathway and P52/RelB-Dependent Gene Expression in Lung Epithelial Cells

Influenza A Virus NS1 Protein Prevents Activation of NF-KB and Induction of Alpha/Beta Interferon

A Site on the Influenza A Virus NS1 Protein Mediates Both Inhibition of PKR Activation and Temporal Regulation of Viral RNA Synthesis

The Primary Function of RNA Binding by the Influenza A Virus NS1 Protein in Infected Cells: Inhibiting the 2'-5' Oligo (A) Synthetase/RNase L Pathway

Influenza virus non-structural protein NS1: Interferon antagonism and beyond

The influenza A virus protein NS1 displays structural polymorphism

The Influenza A Virus NS1 Protein Inhibits Activation of Jun N-Terminal Kinase and AP-1 Transcription Factors

Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus

Sequence of Interrupted and Uninterrupted MRNAs and Cloned DNA Coding for the Two Overlapping Nonstructural Proteins of Influenza Virus

Splicing of Influenza A Virus NS1 MRNA Is Independent of the Viral NS1

Influenza Viruses and MRNA Splicing: Doing More with Less

Emergence of a C-Terminal Seven-Amino-Acid Elongation of NS1 in Around 1950 Conferred a Minor Growth Advantage to Former Seasonal Influenza A Viruses

Mammalian Adaptation of an Avian Influenza A Virus Involves Stepwise Changes in NS1

A Novel RNA-Binding Motif in Influenza A Virus Non-Structural Protein 1

Crystal Structure of the Unique RNA-Binding Domain of the Influenza Virus NS1 Protein

RNA Binding by the Novel Helical Domain of the Influenza Virus NS1 Protein Requires Its Dimer Structure and a Small Number of Specific Basic Amino Acids

A Recombinant Influenza A Virus Expressing an RNA-Binding-Defective NS1 Protein Induces High Levels of Beta Interferon and Is Attenuated in Mice

A Transient Homotypic Interaction Model for the Influenza A Virus NS1 Protein Effector Domain

F NMR Reveals Multiple Conformations at the Dimer Interface of the Nonstructural Protein 1 Effector Domain from Influenza A Virus

Dimer Interface of the Effector Domain of Non-Structural Protein 1 from Influenza A Virus: An Interface with Multiple Functions

Structural basis for dsRNA recognition by NS1 protein of influenza A virus

Two Nuclear Location Signals in the Influenza Virus NS1 Nonstructural Protein

Nuclear and Nucleolar Targeting of Influenza A Virus NS1 Protein: Striking Differences between Different Virus Subtypes

Regulation of a Nuclear Export Signal by an Adjacent Inhibitory Sequence: The Effector Domain of the Influenza Virus NS1 Protein

The Multifunctional NS1 Protein of Influenza A Viruses

Conformational Plasticity of the Influenza A Virus NS1

A New Influenza Virus Virulence Determinant: The NS1 Protein Four C-Terminal Residues Modulate Pathogenicity

Influenza Virus Infection Causes Global RNAPII Termination Defects

Immunomodulatory Nonstructural Proteins of Influenza A Viruses

Influenza A Virus Lacking the NS1 Gene Replicates in Interferon-Deficient Systems

Properties of H7N7 Influenza A Virus Strain SC35M Lacking Interferon Antagonist NS1 in Mice and Chickens

The K186E Amino Acid Substitution in the Canine Influenza Virus H3N8 NS1 Protein Restores Its Ability To Inhibit Host Gene Expression

Influenza A Virus Attenuation by Codon Deoptimization of the NS Gene for Vaccine Development

NS1 Protein Mutation I64T Affects Interferon Responses and Virulence of Circulating H3N2 Human Influenza A Viruses

NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses

Species-Specific Inhibition of RIG-I Ubiquitination and IFN Induction by the Influenza A Virus NS1 Protein

The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3. Front

Virulence Factor Protein Inhibits Innate Immune Response by Targeting IKK

The RNA Binding Domain of Influenza A Virus NS1 Protein Affects Secretion of Tumor Necrosis Factor Alpha, Interleukin-6, and Interferon in Primary Murine Tracheal Epithelial Cells

Epigenetic Modification Is Regulated by the Interaction of Influenza A Virus Nonstructural Protein 1 with the De Novo DNA Methyltransferase DNMT3B and Subsequent Transport to the Cytoplasm for K48-Linked Polyubiquitination

Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins

Interactions Between NS1 of Influenza A Viruses and Interferon-α/β: Determinants for Vaccine Development

Functions of the Influenza A Virus NS1 Protein In Antiviral Defense

Influenza A Virus NS1 Protein Inhibits the NLRP3 Inflammasome

NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

A New Player in a Deadly Game: Influenza Viruses and the PI3K/Akt Signalling Pathway

Influenza A Virus NS1 Protein Activates the Phosphatidylinositol 3-Kinase (PI3K)/Akt Pathway by Direct Interaction with the P85 Subunit of PI3K

Concepts in MDM2 Signaling

Influenza A Virus NS1 Protein Binds P85β and Activates Phosphatidylinositol-3-Kinase Signaling

Structural Insights into Phosphoinositide 3-Kinase Activation by the Influenza A Virus NS1 Protein

Structure-Guided Functional Annotation of the Influenza A Virus NS1 Protein Reveals Dynamic Evolution of the P85β-Binding Site during Circulation in Humans

Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses

Phosphatidylinositol-3-Kinase (PI3K) Is Activated by Influenza Virus VRNA via the Pathogen Pattern Receptor Rig-I to Promote Efficient Type I Interferon Production

Regulation of Influenza A Virus Induced CXCL-10 Gene Expression Requires PI3K/Akt Pathway and IRF3 Transcription Factor

Influenza A Virus-Induced Apoptosis and Virus Propagation

Caspase 3 Activation Is Essential for Efficient Influenza Virus Propagation

Structural Basis for Suppression of a Host Antiviral Response by Influenza A Virus

Cellular Antiviral Responses against Influenza A Virus Are Countered at the Posttranscriptional Level by the Viral NS1A Protein via Its Binding to a Cellular Protein Required for the 3 End Processing of Cellular Pre-MRNAS

Influenza Virus NS1 Protein Interacts with the Cellular 30 KDa Subunit of CPSF and Inhibits 3 End Formation of Cellular Pre-MRNAs

Host Shutoff in Influenza A Virus: Many Means to an End

Pre-MRNA 3 -End Processing Complex Assembly and Function

Influenza A Virus NS1 Protein Targets Poly(A)-Binding Protein II of the Cellular 3 -End Processing Machinery

Influenza Virus NS1 Protein Binds Cellular DNA to Block Transcription of Antiviral Genes

Influenza Virus Targets the MRNA Export Machinery and the Nuclear Pore Complex

Eukaryotic Translation Initiation Factor 4GI Is a Cellular Target for NS1 Protein, a Translational Activator of Influenza Virus

NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

IFNβ Induction by Influenza A Virus Is Mediated by RIG-I Which Is Regulated by the Viral NS1

The Influenza NS1 Protein Modulates RIG-I Activation via a Strain-Specific Direct Interaction with the Second CARD of RIG-I

Structural Basis for a Novel Interaction between the NS1 Protein Derived from the 1918 Influenza Virus and RIG-I

Role of N Terminus-Truncated NS1 Proteins of Influenza A Virus in Inhibiting IRF3 Activation

Influenza A Virus Strains That Circulate in Humans Differ in the Ability of Their NS1 Proteins to Block the Activation of IRF3 and Interferon-β Transcription

Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis

A20 in Inflammation and Autoimmunity

A20 Deficiency in Lung Epithelial Cells Protects against Influenza A Virus Infection

Anti-Viral Tetris: Modulation of the Innate Anti-Viral Immune Response by A20

De-Ubiquitination and Ubiquitin Ligase Domains of A20 Downregulate NF-KappaB Signalling

A20 Is a Potent Inhibitor of TLR3-and Sendai Virus-Induced Activation of NF-KB and ISRE and IFN-β Promoter

The Past Thirty Years and the Next Thirty Years

Unravelling Mechanisms of P53-Mediated Tumour Suppression

Influenza Virus Infection Increases P53 Activity: Role of P53 in Cell Death and Viral Replication

Control of Apoptosis in Influenza Virus-Infected Cells by up-Regulation of Akt and P53 Signaling

Influenza A Virus Induces P53 Accumulation in a Biphasic Pattern

Cellular Transcriptional Profiling in Human Lung Epithelial Cells Infected by Different Subtypes of Influenza A Viruses Reveals an Overall Down-Regulation of the Host P53 Pathway

Emerging Roles of P53 and Other Tumour-Suppressor Genes in Immune Regulation

Interference with P53 Functions in Human Viral Infections, a Target for Novel Antiviral Strategies?

Influenza NS1 Interacts with P53 and Alters Its Binding to P53-Responsive Genes, in a Promoter-Dependent Manner

Influenza A Viruses Control Expression of Proviral Human P53 Isoforms P53β and ∆133p53α

Stabilization of P53 in Influenza A Virus-Infected Cells Is Associated with Compromised MDM2-Mediated Ubiquitination of P53

Influenza A Viruses Alter the Stability and Antiviral Contribution of Host E3-Ubiquitin Ligase Mdm2 during the Time-Course of

P53-Independent Effects of Mdm2

P53-Independent Roles of MDM2 in NF-KB Signaling: Implications for Cancer Therapy, Wound Healing, and Autoimmune Diseases

Modification of Nonstructural Protein 1 of Influenza A Virus by SUMO1

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

A Novel SUMOylation Site in the Influenza a Virus NS1 Protein Identified with a Highly Sensitive FRET Assay

Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection

Species-Specific Antagonism of Host ISGylation by the Influenza B Virus NS1 Protein

Structural Basis for the Sequence-Specific Recognition of Human ISG15 by the NS1 Protein of Influenza B Virus