scholarly journals Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1707
Author(s):  
Pratyusha Mandal ◽  
Lynsey N. Nagrani ◽  
Liliana Hernandez ◽  
Anita Louise McCormick ◽  
Christopher P. Dillon ◽  
...  
Keyword(s):  
Cell Death ◽  
Murine Cytomegalovirus ◽  
Mammalian Host ◽  
Caspase 8 ◽  
Intrinsic Apoptosis ◽  
Pathogen Invasion ◽  
Cell Death Pathways ◽  
Viral Inhibitor ◽  
Extrinsic Apoptosis ◽  
Infected Cells

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochondrial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease enhances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and -independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and supports pathogenesis in the intact mammalian host.

scholarly journals Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways

2017 ◽  
Vol 114 (13) ◽  
pp. E2786-E2795 ◽  
Author(s):  
Lisa P. Daley-Bauer ◽  
Linda Roback ◽  
Lynsey N. Crosby ◽  
A. Louise McCormick ◽  
Yanjun Feng ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Double Mutant ◽  
Kinase Domain ◽  
Murine Cytomegalovirus ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Antiviral Responses ◽  
Cell Death Pathways ◽  
Infected Cells

The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by ΔM36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-in-hand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.

scholarly journals Mitochondrial Cell Death Suppressors Carried by Human and Murine Cytomegalovirus Confer Resistance to Proteasome Inhibitor-Induced Apoptosis

2005 ◽  
Vol 79 (19) ◽  
pp. 12205-12217 ◽  
Author(s):  
A. Louise McCormick ◽  
Christopher D. Meiering ◽  
Geoffrey B. Smith ◽  
Edward S. Mocarski
Keyword(s):  
Cell Death ◽  
Viral Genome ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Murine Cytomegalovirus ◽  
Viral Inhibitor ◽  
Infected Cells ◽  
Induced Apoptosis ◽  
Functional Copy ◽  
Inactivating Mutations

ABSTRACT Human cytomegalovirus carries a mitochondria-localized inhibitor of apoptosis (vMIA) that is conserved in primate cytomegaloviruses. We find that inactivating mutations within UL37x1, which encodes vMIA, do not substantially affect replication in TownevarATCC (Towne-BAC), a virus that carries a functional copy of the betaherpesvirus-conserved viral inhibitor of caspase 8 activation, the UL36 gene product. In Towne-BAC infection, vMIA reduces susceptibility of infected cells to intrinsic death induced by proteasome inhibition. vMIA is sufficient to confer resistance to proteasome inhibition when expressed independent of viral infection. Murine cytomegalovirus m38.5, whose position in the viral genome is analogous to UL37x1, exhibits mitochondrial association and functions in much the same manner as vMIA in inhibiting intrinsic cell death. This work suggests a common role for vMIA in rodent and primate cytomegaloviruses, modulating the threshold of virus-infected cells to intrinsic cell death.

Genetic Regulation of RIPK1 and Necroptosis

2021 ◽  
Vol 55 (1) ◽  
pp. 235-263
Author(s):  
Daichao Xu ◽  
Chengyu Zou ◽  
Junying Yuan
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genetic Regulation ◽  
Caspase 8 ◽  
Inflammatory Signaling ◽  
Interacting Protein ◽  
Multiple Factors ◽  
Cell Death Pathways ◽  
Upstream Regulator ◽  
Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

scholarly journals The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1313
Author(s):  
Man Wang ◽  
Shuai Jiang ◽  
Yinfeng Zhang ◽  
Peifeng Li ◽  
Kun Wang
Keyword(s):  
Cell Death ◽  
Biological Significance ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Cell Swelling ◽  
Pathogen Invasion ◽  
Membrane Rupture ◽  
Cancer Management ◽  
Cell Death Pathways ◽  
Cancer Pathogenesis

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

scholarly journals DOP86 An IFN-STAT1-MLKL axis drives programmed necrosis of Paneth cells in Crohn’s ileitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S125-S126
Author(s):  
L HARTMANN ◽  
B Siegmund ◽  
C Weidinger ◽  
C Becker ◽  
M F Neurath ◽  
...  
Keyword(s):  
Cell Death ◽  
Intestinal Inflammation ◽  
Paneth Cell ◽  
Signalling Pathways ◽  
Caspase 8 ◽  
Programmed Necrosis ◽  
Cell Death Pathways ◽  
Small Intestinal

Abstract Background Interferons (IFNs) are immune-modulatory cytokines expressed by epithelial and mucosal cells in response to viral and bacterial infection. Just recently, we discovered a correlation between IFN-λ expression and disease activity, including small intestinal inflammation and Paneth cell dysfunction, in human Crohn’s disease patients. On a molecular level, we uncovered that IFN-λ mediates epithelial cell death, in particular, Paneth cell death by a programmed necrosis, dependent on STAT1 activation and controlled by caspase-8. These results suggested that IFN-λ can be considered as a pathogenic cytokine in Crohn′s ileitis and should be considered as a new and promising target for future therapeutic intervention for this particular subtype of IBD. Our central question is now by which pathways interferon-regulated programmed necrosis of epithelial cells contributes to intestinal inflammation and how these mechanisms could be targeted for future therapeutic intervention. Methods We use a mouse model for Crohn’s Disease like inflammation and Paneth cell death that has a specific deletion of Caspase-8 in intestinal epithelial cells (Casp8∆IEC). We stimulate small intestinal organoids derived from Casp8∆IEC mice with IFNs in vitro and we overexpress IFN-λ in these mice in vivo by hydrodynamic tail vein injection of an IFN-λ expression vector. Furthermore, we use JAK-inhibitors to impede pharmacologically cell death pathways in the pathogenesis of intestinal inflammation in vitro and in vivo. Results We uncovered that gene expression of the cell death mediators Mlkl and Caspase-8 is dependent on IFN-λ-mediated JAK-STAT1 signalling. The non-specific pan JAK-inhibitor Tofacitinib is able to attenuate gene expression of Mlkl and Caspase-8 in vitro as well as in vivo. It prevents non-apoptotic as well as apoptotic cell death of small intestinal organoids stimulated with IFN-λ and is sufficient to prevent small intestinal tissue destruction in Casp8∆IEC mice challenged with IFN-λ. Additionally, we use the selective JAK1-inhibitor Filgotinib to limit the targeted JAK-STAT signalling pathways to only JAK1-STAT1 signalling and thus reduce side effects of the inhibitor on other signalling pathways. This had a similar effect as Tofacitinib suggesting that IFN controls MLKL-mediated cell death via JAK1. Conclusion In summary, our results indicate that targeting IFN-λ-mediated JAK-STAT1 signalling by the small-molecules Tofacitinib and Filgotinib impedes induction of Mlkl and Caspase-8-mediated cell death pathways. Therefore, JAK1 inhibitors such as Filgotinib might represent a promising novel therapy that may be sufficient to achieve efficacy particularly in Crohn′s ileitis patients who display elevated IFN-l serum levels.

scholarly journals Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1827 ◽  
Author(s):  
Khurshid Ahmad ◽  
Vishal M. Balaramnavar ◽  
Navaneet Chaturvedi ◽  
Saif Khan ◽  
Shafiul Haque ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Structural Information ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Caspase 8 ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Zinc Database ◽  
Dynamics Simulations

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.

Activity of caspase-8 determines plasticity between cell death pathways

Nature ◽  
2019 ◽  
Vol 575 (7784) ◽  
pp. 679-682 ◽  
Author(s):  
Kim Newton ◽  
Katherine E. Wickliffe ◽  
Allie Maltzman ◽  
Debra L. Dugger ◽  
Rohit Reja ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 8 ◽  
Cell Death Pathways

scholarly journals Innate Immune sensing of Influenza A viral RNA through IFI16 promotes pyroptotic cell death

2021 ◽  
Author(s):  
Shalabh Mishra ◽  
Athira S Raj ◽  
Akhilesh Kumar ◽  
Ashwathi Rajeevan ◽  
Puja Kumari ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Type I ◽  
Cell Death Pathways ◽  
Infected Cells ◽  
Immune Sensing

AbstractProgrammed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus IAV infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for influenza A virus by binding to genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). Whereas, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. These results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2376-2384 ◽  
Author(s):  
Soizic Daniel ◽  
Maria B. Arvelo ◽  
Virendra I. Patel ◽  
Christopher R. Longo ◽  
Gautam Shrikhande ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Killer Cell ◽  
Nuclear Factor Κb ◽  
Caspase 8 ◽  
Apoptotic Pathway ◽  
Cell Death Pathways ◽  
Executioner Caspases ◽  
First Time ◽  
Necrosis Factor

Abstract A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)–mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor–κB (NF-κB). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell–mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders.

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