key: cord-0866309-ckfaonn6
authors: Nhat Nguyen, Lam; Kanneganti, Thirumala-Devi
title: PANoptosis in viral infection: The missing puzzle piece in the cell death field
date: 2021-09-16
journal: J Mol Biol
DOI: 10.1016/j.jmb.2021.167249
sha: 8d2853867b0b65db91bd0b8e15f5c1a0755efaa4
doc_id: 866309
cord_uid: ckfaonn6

In the past decade, emerging virus outbreaks like SARS-CoV-2, Zika and Ebola have presented major challenges to the global health system. Viruses are unique pathogens in that they fully rely on the host cell to complete their lifecycle and potentiate disease. Therefore, programmed cell death (PCD), a key component of the host innate immune response, is an effective strategy for the host cell to curb viral spread. The most well-established PCD pathways, pyroptosis, apoptosis and necroptosis, can be activated in response to viruses. Recently, extensive crosstalk between PCD pathways has been identified, together with evidence that molecules from all three PCD pathways can be activated during virus infection. These findings have led to the emergence of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. While PCD is important to eliminate infected cells, many viruses are equipped to hijack host PCD pathways to benefit their own propagation and subvert host defense, and PCD can also lead to the production of inflammatory cytokines and inflammation. Therefore, viral infection can induce PANoptosis to contribute to either host defense or viral pathogenesis, depending on the virus. In this review, we will discuss the multi-faceted roles of PCD pathways in controlling viral infections.

Viral infections pose a significant global health threat, as seen by the ongoing coronavirus disease 2019 (COVID- 19) pandemic, which is caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Beyond SARS-CoV-2, several other viruses have also caused recent outbreaks, including influenza, Ebola, and Zika, and many more continue to circulate and cause morbidity and mortality around the globe. In mammals, innate immunity stands as the first line of defense during viral infections. Upon infection, viral pathogen-associated molecular patterns (PAMPs) are sensed by host pattern recognition receptors (PRRs), including the membrane-bound Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) and the cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acidinducible gene-I (RIG-I)-like receptors (RLRs), and absent in melanoma 2 (AIM2)-like receptors (ALRs). PRR detection of viral PAMPs triggers the activation of the innate immune signaling pathways, such as transcription factor NF-B and mitogen-activated protein (MAP) kinase signaling to produce inflammatory cytokines and interferons and prime the immune response [1] .

Activation of PRRs can often lead to diverse forms of cell death [2] . At the cellular level, elimination of infected host cells through programmed cell death (PCD) pathways is crucial to stop viral spread, as viruses are intracellular pathogens that are entirely dependent on host cells for their propagation. On the other hand, at the organism level, cell death can contribute to disease pathogenesis during viral infections; inflammatory products such as damage-associated molecular patterns (DAMPs), alarmins, additional PAMPs and inflammatory cytokines are released from the dying cells and can go on to trigger inflammatory cytokine storms, organ damage, and lethality [3] [4] [5] . Therefore, the activation of cell death must be carefully balanced for optimal host defense.

The most well-defined PCD pathways include pyroptosis, apoptosis, and necroptosis, and each has been reported to be activated in many viral infections. Furthermore, viral infections can also elicit multiple cell death pathways, as seen with influenza virus (IAV) infections [6] [7] [8] [9] and In dengue virus infection, inflammasome activation and pyroptosis have been reported in multiple cell types including macrophages, dendritic cells, platelets, and neutrophils [52] . C-type lectin domain family member A (CLEC5A) acts as a PRR to mediate dengue virus-induced NLRP3 inflammasome activation [53] . The expression of CLEC5A and NLRP3 is higher in activated macrophages compared to resting macrophages. Upon dengue infection, NLRP3 expression is upregulated, while expression of other NLR sensors such as NLRC4 and NLRP1 is unchanged.

In addition, knockdown of NLRP3 using siRNA reduced dengue infection-induced cleavage of caspase-1 and IL-1β and IL-18 release [53] .

Another member of the Flaviviridae family, Zika virus, also induces pyroptotic death in neural progenitor cells, as evidenced by the cleavage of caspase-1 and GSDMD and the increase in IL-1β and IL-18 release [54] . Similar to the upregulation of NLRP3 expression observed during dengue virus infection, neural progenitor cells upregulate expression of NLRP3 but not NLRC4, AIM2, or Pyrin during Zika infection, suggesting that Zika infection-induced inflammasome activation is likely to be NLRP3-dependent [54] . Furthermore, in a Zika-infected mouse model, genetic deletion of caspase-1 or treatment with the caspase-1 inhibitor VX-765, but not the caspase-3 inhibitor Z-DEVD-FMK, significantly reduces brain atrophy-induced microcephaly [54] , further highlighting the role of inflammasome activation in the infection.

Activation of the inflammasome has also been reported in coronavirus infections [16, 55, 56] including infections with the newly emerging SARS-CoV-2 [57, 58] . In primary human monocytes, SARS-CoV-2 infection induces the formation of an NLRP3 puncta, and NLRP3-positive cells can be found in the lung tissue of patients who have succumbed to COVID-19 [57] . Furthermore, inflammasome-associated inflammatory products in the plasma from patients with COVID-19, such as active caspase-1, IL-18 [57] , LDH, and GSDMD [58] , are positively correlated with disease severity [57, 58] .

While it is clear there are many examples of inflammasome and pyroptosis activation during viral infections, viruses can also directly interfere with pyroptotic cell death by regulating inflammasome activation or targeting the pyroptotic executer GSDMD. In Sendai virus infection, Sendai virus V protein can directly bind to NLRP3 and inhibit NLRP3 self-oligomerization and NLRP3-ASC speck assembly, leading to a reduction in IL-1β release [59] . The V proteins of Nipah virus and human parainfluenza virus type 2 can also interact with NLRP3 to inhibit inflammasome activation, suggesting that the ability to interfere with NLRP3 inflammasome activation and pyroptosis is conserved among V protein-containing viruses (Figure 1 ) [59] . In enterovirus 71 (EV71) infection, mouse strains that are deficient in NLRP3 inflammasome activation, such as Nlrp3 -/-, Asc -/-, and Casp1 -/-mice, develop more severe viral disease compared with wild-type mice, suggesting that NLRP3 inflammasome activation is important for host defense against EV71 infection [60] . To overcome this host defense strategy, the EV71 viral protease 3C interacts with and cleaves NLRP3 to inhibit NLRP3 inflammasome activity to potentiate viral disease [61] . In addition, the EV71 protease 3C cleaves GSDMD to form an N-terminal fragment that is unable to trigger pyroptosis [60] , suggesting that the EV71 3C protease inactivates GSDMD and prevents pyroptosis (Figure 1 ). These and many other virulence and immune evasion strategies allow viruses to subvert host PCD-induced inflammation and coordination of a successful immune response, maximizing the virus's chances of survival at the expense of the host.

Apoptosis has historically been characterized as "immunologically silent" PCD; however, more recent evidence suggests that it can also be inflammatory, with key apoptotic regulators activating inflammatory mechanisms [18, 24, 26, [62] [63] [64] [65] . Cells undergoing apoptosis exhibit morphological changes including nuclear and chromatin condensations, DNA fragmentation, and membrane blebbing to form apoptotic bodies which are cleared upon engulfment by phagocytes [66] .

Apoptosis can be initiated through extrinsic or intrinsic pathways. The extrinsic pathway is initiated by signals from outside the cell through the binding of death ligands such as Fas ligand (FasL), tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) to their respective receptors. Receptor engagement triggers the formation of the death-inducing signaling complex (DISC), comprising Fas-associated death domain (FADD) and pro-caspase-8, through homotypic interactions and leads to caspase-8 activation [67] . Activation of caspase-8 is tightly regulated by the anti-apoptotic cellular FADD-like IL-1β-converting enzyme inhibitory protein (cFLIP), which binds to FADD and/or caspase-8 to form an apoptosis inhibitory complex [68] . Activated caspase-8 can directly proteolytically activate effectors and the executioners caspases-7 and -3 to induce apoptosis [69] , or it can indirectly induce intrinsic apoptosis by cleaving the BH3-only protein BID to its active form tBID, and driving the BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP)-induced apoptosis (Figure 2 ) [70, 71] .

Unlike extrinsic apoptosis, which requires the presence of external ligands, intrinsic apoptosis is activated by nutrient or growth factor withdrawal, DNA damage, or other internal cellular stresses. These events trigger the expression of pro-apoptotic members of the BCL-2 family including BIM, NOXA, PUMA, and BAD, which bind and neutralize the pro-survival BCL-2 family BH3-only proteins such as BCL-2, BCL-XL, MCL-1, and BCL-2-related protein A1 (BCL-2A1), freeing the BAK/BAX complex to induce MOMP and release cytochrome c [72] . The binding of cytochrome c to the apoptotic peptidase activation factor 1 (APAF-1) in the cytoplasm prompts apoptosome formation, leading to the activation of initiator caspase-9 to induce activation of caspases-7 and -3 to drive apoptosis (Figure 2 ) [73] . To keep the system in balance, the inhibitor of apoptosis proteins (IAPs), such as X-linked inhibitor of apoptosis (XIAP), can promote proteasomal degradation of caspases to inhibit apoptosis [74] . These IAPs can be blocked by MOMP-induced second mitochondrial activator of caspases (SMAC/DIABLO) and HTRA serine peptidase 2 (HTR2) to release the brake on cell death and facilitate apoptosis [75] .

Apoptosis is the most studied PCD in viral infections. Pro-apoptotic signaling is associated with nearly all stages of viral infection. At the viral entry stage, the binding of avian leukosis virus (ALV) envelop protein to the cytopathic ALSV receptor (CAR1) or the binding of bovine herpesvirus (BHV-1) glycoprotein gD to the herpesvirus entry mediator (HVEM) is sufficient to induce apoptosis [76, 77] . Although detailed mechanisms have not been characterized, given that CAR1 and HVEM are death receptors themselves, extrinsic apoptosis likely plays important roles in the cell death induced by these viral attachments.

After the virus has entered the cell, sensing of the viral genomes by host PRRs to initiate apoptotic cell death is an extensively studied component of the innate immune response to viral infection. Viral genomes can be sensed in many forms, including viral DNA (vDNA), cDNA synthesized from viral RNA (v-cDNA), and viral single-stranded or double-stranded RNA (vRNA). [79, 80] . In addition, IRF3 mutants that lack transcription factor activity can interact with BAX to induce translocation of IRF3-BAX to the mitochondria, triggering intrinsic apoptosis in Sendai and human T cell leukemia virus (HTLV) infections [81, 82] . In the context of IRF3-mediated, transcription-dependent apoptosis, IRF3 drives the expression of the death ligand TRAIL [83] and BH3-only protein NOXA [84] in Sendai and reovirus infections, respectively, to trigger apoptosis.

The sensing of viral genome by PRRs also triggers a cascade of adapter protein interactions.

For example, RIG-I sensing of short 5'-triphosphate (ppp) viral dsRNA leads to an ATP-dependent conformational change and the formation of a filamentous tetramer of RIG-I through CARD-CARD homotypic interactions [85] . The K63-ubiqitin chain linked to the RIG-I tetramer N-terminal CARDs forms oligomers with the CARD in the adaptor protein MAVS [86] , recruiting downstream adaptors such as TNFR-associated factor 6 (TRAF6) or TNFR-associated factor 3 (TRAF3) [87, 88] to activate NF-B, IRF3, and IFN regulatory factor 7 (IRF7) and induce inflammatory cytokine and chemokine production and type I and III IFN responses. This signaling process positively regulates apoptosis (Figure 2) . Indeed, IFN-α/β signaling through the IFN-α/β receptor (IFNAR) activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway to upregulate IFN-stimulated genes (ISGs) and promote apoptosis [89] . For example, the activity of the ISG protein kinase R (PKR) is stimulated after sensing dsRNA and subsequently phosphorylates translational initiation factor eIF2a, blocking cellular translation and facilitating apoptosis [90] . PKR also can induce apoptosis independently with its ability to inhibit translation through the FADD-caspase-8/-3 axis [91] . Another ISG, 2', 5'-oligoadenylate synthetase (OAS), detects dsRNA and activates the ISG RNase L to degrade host and viral RNA, resulting in apoptosis [92] . IFN signaling can also induce p53 activation, which drives apoptosis through p53 transcriptional activity inducing pro-apoptotic BH3-only proteins PUMA and NOXA [93] .

Apoptotic cell death also plays an important role in cytotoxic T lymphocyte (CTL) and natural killer (NK) cell killing of viral infected cells to control virus infection. CTLs and NK cells produce and store perforin, a membrane pore-forming protein, and granzymes, serine proteases, in cytotoxic granules. Upon detection of virally infected cells, CTLs or NK cells target the infected cells and release cytotoxic granules, liberating granzymes into the cytoplasm of targeted cells and facilitating perforin oligomerization and the formation of a membrane attack complex to initiate intrinsic apoptosis (Figure 2 ) [94] . CTLs can also induce extrinsic apoptosis in virally infected cells through the engagement of FAS ligand on CTLs and FAS receptor on targeted cells [95] .

To enable immune evasion and viral survival strategies, many viruses encode virulence proteins that inhibit apoptotic death, such as caspase inhibitors. Examples include the murine cytomegalovirus (MCMV) vICA protein, which inhibits caspase-8 [96] , and the cowpox virus CrmA protein, which inhibits caspase-8 and granzyme B (Figure 2) [97, 98] . In addition to caspase inhibitors, viruses can also encode Bcl-2 homologs to block Bax-and Bak-mediated MOMPdependent apoptosis, such as the Adenovirus E1B19K [99] and the Epstein-Barr virus BHRF1 and BALF1 [100, 101] . Despite these attempts by the virus to evade cell death, viral blockade of apoptosis commonly leads to the activation of alternative PCD pathways by host cells, highlighting the interconnection of PCD pathways, which will be discussed in detail later in this review.

Necroptosis is an additional PCD pathway that was often considered as a fail-safe to allow cell death to proceed in conditions where apoptosis was inhibited. Therefore, the signaling pathways involved in apoptosis and necroptosis have long been known to be intricately linked. (Figure 3) . Phosphorylated MLKL is oligomerized to become a multimeric complex that disrupts the plasma membrane and leads to necroptotic cell death [106] . The formation of the RIPK1-RIPK3 necrosome complex, in most physiological conditions, is inhibited by the cFLIP/caspase-8 heterodimeric complex, which is recruited to the RIPK1-RIPK3 complex through the adapter FADD and can cleave both RIPK1 and RIPK3 to prevent necroptosis and promote apoptosis (Figure 3 ) [103, 104, 107] . Thus, inhibition of caspase-8, as occurs in response to viral effectors such as the MCMV vICA protein [96] , is a key event triggering necroptosis. Alternatively, necroptosis can also be activated by the sensor Z-DNA-binding protein 1 (ZBP1), an ISG that contains RHIM domains to recruit and activate RIPK3induced MLKL phosphorylation resulting in cell death [6, 10, 108, 109] . ZBP1-mediated cell death has been reported in various viral infections including cytomegalovirus (CMV) [108] , herpes simplex virus (HSV) [10] , vaccinia virus (VACV) [109] , West Nile virus (WNV) [110] , Zika virus [111] , and IAV [6] . In addition to its role in necroptosis, ZBP1 is also critically involved across PCD pathways [6] , which will be discussed in depth in the next section.

As is the case with other PCD pathways, many viruses are equipped with viral proteins to inhibit cellular necroptosis. VACV viral protein E3L has an N-terminal Z domain similar to that found in ZBP1 that can compete with ZBP1 to inhibit the ZBP1-RIPK3 axis and block necroptosis [112] . Additionally, the MCMV viral protein M45 contains a RHIM domain, which can interfere with the RHIM-RHIM interaction between ZBP1 and RIPK3, leading to necroptosis inhibition ( Figure   3 ) [113] . Recent evidence also suggests that some viruses can lead to elimination of RIPK3, as the viral inducer of RIPK3 degradation (vIRD) from cowpox virus and other orthopoxviruses induces the proteasomal degradation of RIPK3 to inhibit necroptosis [114] .

Clearance of infected cells is the ultimate goal to enable the host to survive pathogen infection.

To counteract this strategy, intracellular pathogens such as viruses are equipped to hijack host cell death pathways to support their own propagation. Virus-mediated inhibition of one PCD pathway could evolutionarily favor the development of mechanisms that would potentiate other cell death executioners and effectors through a shared signaling scaffold under these conditions, underscoring the importance of understanding the interconnections between PCD pathways. As discussed above, apoptosis and necroptosis are both regulated by caspase-8 activity. In a physiological context, canonical signals from death receptors can trigger extrinsic apoptosis through the activation of caspase-8, which in turn also cleaves RIPK1 or/and RIPK3 to prevent necroptosis (Figure 3) . The crosstalk between PCD pathways mediated through caspase-8 has been further shown through its connection with inflammasome activation and pyroptosis.

Caspase-8 mediates the priming and activation of the canonical and noncanonical NLRP3 inflammasomes [26] . Furthermore, caspase-8 can associate with the inflammasome adapter ASC [115] , and induce cleavage of GSDMD to trigger pyroptosis [29, 116, 117] . The ASC-dependent activation of caspase-8 also can trigger apoptosis in the absence of caspase-1 [118] . Molecular connections between these PCD pathways that go beyond caspase-8 have also been found. The apoptotic caspase-7 can be cleaved by caspase-1 downstream of inflammasome activation [25] , and the NLRP3 and NLRC4 inflammasomes can result in the cleavage of the apoptotic marker PARP1 [19] . Additionally, inflammasome-induced caspase-1 activation can trigger apoptosis in the absence of GSDMD through the BID, caspase-9, and caspase-3 axis [119] . Activated caspase-3 can also cleave GSDME, a pore-forming protein belonging to the gasdermin protein family, triggering pyroptotic cell death [65, 119] .

In the context of viral infection, evidence for crosstalk between PCD pathways has been the most well characterized with IAV infection. During IAV infection, ZBP1 acts as the upstream sensor to induce cell death with biochemical characteristics of pyroptosis, apoptosis, and necroptosis [6] . Deletion of ZBP1 can inhibit activation of all these PCD pathways, including NLRP3 inflammasome-induced pyroptosis, RIPK1-RIPK3 necrosome-induced necroptosis, and caspase-8-driven apoptosis. However, individual deletion of any of the PCD pathways in isolation does not protect against cell death; IAV infection-induced ZBP1-dependent cell death is only prevented in cells lacking both RIPK3 and caspase-8 (Figure 4) [6, 8] . These findings suggest that ZBP1 acts as a master regulator of a unique inflammatory PCD pathway that contemporaneously engages key molecules from pyroptosis, apoptosis and/or necroptosis, establishing the existence of PANoptosis during viral infection (Figure 4) . More recent studies have built upon this initial evidence to describe an important role for caspase-6 in promoting the interaction between ZBP1 and RIPK3 and to characterize the formation of a multi-protein complex that contains ZBP1, RIPK3, RIPK1, caspase-8, ASC, and NLRP3, defined as the ZBP1-PANoptosome, to regulate PANoptosis (Figure 4) [9, 27, 120, 121] . [16] . In vesicular stomatitis virus (VSV) infection, PANoptosis is also observed, and blocking a single PCD, such as deletion of caspase-1/11, GSDMD, GSDMD/MLKL, or RIPK3, cannot prevent cell death. As is the case during MHV infection, VSV-induced cell death is significantly reduced in the combined absence of caspase-8 and RIPK3 [122] .

In addition to these viruses that are known to induce PANoptosis, several viruses have been shown to activate multiple PCD pathways and to carry viral proteins that influence the biochemical cell death outcome. The HSV1 and HSV2 viral protein ICP6 contains a RHIM domain, which can bind to both RIPK1 and RIPK3 in mouse cells, triggering necrosome assembly and necroptotic cell death [123] . By contrast, in human cells, ICP6 binds to both RIPK1 and RIPK3 and disrupts their interaction to block necrosome formation [11] . Furthermore, human cells expressing ICP6 without the C-terminal, which is responsible for caspase-8 binding, undergo apoptotic death, while cells expressing ICP6 lacking the N-terminal, containing the RHIM domain, undergo necroptotic death [11] . Recent reports also show that HSV infection can activate the inflammasome in central nervous system (CNS)-resident macrophages, microglia, as deletion of ASC significantly reduces HSV infection-induced CNS inflammation [12] . Thus, multiple PCD pathways can be triggered during HSV infection, and the virus itself carries proteins that modulate PCD activation. Whether this is PANoptosis remains to be determined.

In the case of CMV, viral protein pUL36, encoded by the UL36 gene, interacts with procaspase-8 and inhibits caspase-8 activation, blocking apoptosis. CMV pUL36 also blocks necroptosis by inducing MLKL degradation [124] . Other studies have found that CMV infection can induce both caspase-1 and caspase-11 activation and cleavage of GSDMD to cause pyroptosis-driven inflammation in an induced retinitis model in immunosuppressed mice [125, 126] .

In addition to viruses that directly activate PANoptosis, virus-induced signaling and cytokine release can also drive PANoptosis. One key example of this occurs during SARS-CoV-2 infection.

A prominent feature of severe COVID-19 pathology is cytokine storm, which can cause severe inflammation and lethality in patients [3] . Two of the key cytokines produced during cytokine storms are TNF-α and IFN-γ. Administration of TNF-α and IFN-γ in mice can mimic the clinical symptoms of COVID-19 [4] , highlighting their importance in disease pathogenesis. Together, these two cytokines can drive PANoptosis and tissue and organ damage [4] . These findings led to the definition of cytokine storm as a life-threatening condition caused by excessive production of cytokines mediated by inflammatory cell death, PANoptosis [5] . Treatment of mice with neutralizing antibodies against TNF-α and IFN-γ provides protection during SARS-CoV-2 infection [4] , suggesting that these two cytokines and their induction of PANoptosis are a driving force in COVID-19 pathology. 

Viruses are intracellular pathogens that require host cell machinery to advance their lifecycle.

Due to this unique lifestyle, the survival of infected cells is necessary for viral spread. Thus, successful activation of any PCD pathway can de-rail virus survival by limiting its replicative niche and also by exposing the virus to the immune system. PCD is an effective host defense strategy, but hyperactivation of the antiviral response and inflammatory PCD can lead to systemic inflammation and pathology. Therefore, the host must carefully balance PCD activation to prevent excess inflammation while clearing the infection and blocking viral disease potentiation.

involving key molecules from pyroptosis, apoptosis, and/or necroptosis, and PANoptosis has now been implicated in viral infections as well as in bacterial and fungal infections, cancer, and autoinflammatory diseases [2, 5, 6, 13-18, 20-24, 26, 27, 127-130] . These discoveries have transformed our understanding of PCD pathways and showed that a signaling complex containing initiators and effectors of pyroptosis, apoptosis, and necroptosis, such as ASC/caspase-1, caspase-8, and RIPK1-RIPK3, can be formed (PANoptosome). This formation is likely to be context-and cell type-specific, with different sensors involved depending on the stimuli present.

Viruses have an extraordinary ability to block PCD, which could emerge troublesome for the immune system to contain viral diseases, and PANoptosis may serve as a mechanistic strategy to overcome the inhibition of PCD. Future studies on how the host immune system detects virally infected cells to activate or inhibit PANoptosis will help inform the development of therapeutic agents to selectively inhibit or activate PANoptosis for the benefit of the host immune system to contain and clear infected cells and limit systemic inflammation. into bioactive inflammatory cytokines. Simultaneously, active caspase-1 cleaves GSDMD to free the pore-forming N-terminal fragment (N-GSDMD) to assemble membrane pores and initiate the releases of active IL-1β and IL-18 and induce pyroptotic cell death. The Sendai and Nipah viral protein V can directly bind to NLRP3 to inhibit NLRP3 self-oligomerization and prevent the assembly of NLRP3 and ASC to activate inflammasome. Additionally, the EV71 protease 3C can cleave either NLRP3 or GSDMD to inhibit pyroptosis. Created with BioRender.com 

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p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa

Functional significance of the perforin/granzyme cell death pathway

Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways

A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation

Granzyme B is inhibited by the cowpox virus serpin cytokine response modifier A

Target protease specificity of the viral serpin CrmA. Analysis of five caspases

Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells

Epstein-Barr viruscoded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death

Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1

RIPK1 Kinase-Dependent Death: A Symphony of Phosphorylation Events

Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis

Mixed Lineage Kinase Domain-like Protein MLKL Causes Necrotic Membrane Disruption upon Phosphorylation by RIP3

Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis

DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA

Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation

Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation

The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons

Inhibition of DAIdependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3

Virus inhibition of RIP3-dependent necrosis

A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation

Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex

Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC

Caspase-1 initiates apoptosis in the absence of gasdermin D

Newly Identified Function of Caspase-6 in ZBP1-mediated Innate Immune Responses, NLRP3 Inflammasome Activation, PANoptosis, and Host Defense

The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

Identification of the PANoptosome: A molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis). Frontiers in cellular and infection microbiology

Initiates Necroptosis to Restrict Virus Propagation in Mice

Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor

Atypical cytomegalovirus retinal disease in pyroptosis-deficient mice with murine acquired immunodeficiency syndrome

Stimulated Intraocularly in Mice with Retrovirus-Induced Immunosuppression (MAIDS) During Experimental Murine Cytomegalovirus (MCMV) Retinitis

PANoptosis components, regulation, and implications

The innate immune system and cell death in autoinflammatory and autoimmune disease

The PANoptosome: A deadly protein complex driving pyroptosis, apoptosis, and necroptosis (PANoptosis). Frontiers in cellular and infection microbiology

:e1009358. which can associate with FADD and caspase-8. Caspase-8 can also be associated with ASC, a core component of the inflammasome, recruiting NLRP3 and caspase-1. The executioners GSDMD, caspase-3 and -7, and MLKL are all activated in response to PANoptosome formation to drive PANoptosis

We apologize to our colleagues in the field whose work could not be cited due to space limitations.We thank all members of the Kanneganti laboratory for their comments and suggestions and R.Tweedell for scientific editing and writing support. Work from our laboratory is supported by the