Programmed Necrosis in Host Defense

Mocarski, Edward S.

doi:10.1007/82_2023_264

Cited by 3 publications

(2 citation statements)

References 253 publications

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“…Nucleic acids (NAs), particularly double-stranded RNA (dsRNA) and dsDNA from pathogens, are detected by pattern recognition receptors to generate interferons (IFNs), which provide host defense against invading microbes 1 . Additionally, the sensors can also recognize endogenous NAs, leading to sustained and profound IFN production in various autoimmune diseases 2 .…”

Section: Introductionmentioning

confidence: 99%

A ZBP1 isoform blocks ZBP1-mediated cell death

Cai,

Wu,

et al. 2024

Preprint

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SummaryZBP1 is an interferon-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA), a type of left-handed nucleic acid. More than that, the binding of ZBP1 with Z-NA promotes cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppresser of the inflammatory signaling mediated by full-length ZBP1. Compared with ZBP1, ZBP1-S protein has Zα domains but no RHIM domains. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Rip1D325A/D325A) with Cleavage-resistant RIP1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-depedent cell death. Intriguingly,Rip1D325A/D325Acells go death spontaneously when ZBP1-S was deleted, indicating the cell death driven by ZPB1 is under the check of ZBP1-S. Thus, our findings reveal that alternative splicing ofZbp1represents an autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against auto-inflammations.HighlightZBP1-short isoform is expressed synchronously with ZBP1.ZBP1-short isoform counteracts ZBP1 mediated cell death.ZBP1-S suppresses ZBP1 signaling in an Zα-domain dependent manner.ZBP1-S prevents the autoactivation of ZBP1 inRip1D325A/D325Acells.

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Section: Introductionmentioning

confidence: 99%

A ZBP1 isoform blocks ZBP1-mediated cell death

Cai,

Wu,

et al. 2024

Preprint

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“…On the other hand, dsRNA-activated OAS impedes translation by synthesizing 2′-5′-linked oligoadenylates and activating the latent endoribonuclease RNase L, which degrades RNA of both cellular and viral origin, leading to inhibition of viral replication [26]. ZBP1 and ADAR1 are the only two mammalian proteins that contain a Z-DNA Zα-domain, and mutation or absence of ADAR1 has been shown to lead to accumulation of Z-RNA, which subsequently activates ZBP1 and induces NF-κB activation (at least in human cells), necroptosis or apoptosis via the receptor-interacting serine/threonine protein kinase -3 (RIPK3) pathway [27][28][29] [30]. Finally, dsRNA-dependent protein kinase (PKR) is a major mediator of the antiviral and inflammatory response, and a number of viruses have been found to encode proteins that inhibit PKR signaling.…”

Section: Introductionmentioning

confidence: 99%

ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication

Parchure,

Cesarec,

Ivanišević

et al. 2024

Preprint

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Adenosine deaminase acting on dsRNA 1 (ADAR1) catalyzes the deamination of adenosines to inosines in double-stranded RNAs (dsRNA) and regulates innate immunity by preventing the hyperactivation of cytosolic dsRNA sensors such as MDA5, PKR or ZBP1. ADAR1 has been shown to exert pro- and antiviral, editing-dependent and editing-independent functions in viral infections, but little is known about its function in herpesvirus replication. We now demonstrate that herpes simplex virus 1 (HSV-1) hyperactivates PKR in the absence of ADAR1, resulting in eIF2a mediated translational arrest and reduced viral replication. Silencing of PKR or inhibition of downstream signaling pathways by viral (ICP34.5) or pharmacological (ISRIB) inhibitors rescues viral replication in ADAR1-deficient cells. Upon infection, ADAR1 p150 directly interacts with PKR and prevents its overactivation. Our findings demonstrate that ADAR1 is an important proviral factor that raises the activation threshold for sensors of innate immunity.

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Cytomegalovirus inhibitors of programmed cell death prevent a contribution of antigen cross-presentation to the priming of antiviral CD8 T cells

Ebert,

Böhm,

Büttner

et al. 2024

Preprint

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CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity spectrum of the CD8 T-cell response. Own recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death caused by deletion of either M36 or M45 improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.

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Programmed Necrosis in Host Defense

Cited by 3 publications

References 253 publications

A ZBP1 isoform blocks ZBP1-mediated cell death

A ZBP1 isoform blocks ZBP1-mediated cell death

ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication

Cytomegalovirus inhibitors of programmed cell death prevent a contribution of antigen cross-presentation to the priming of antiviral CD8 T cells

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