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Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways

Nature Reviews Immunology volume 12, pages 79–88 (2012)Cite this article

Subjects

Key Points

  • Apoptosis and programmed necrosis are common host defence signalling pathways that contribute to the elimination of intracellular pathogens.

  • Caspase 8 promotes apoptosis and suppresses programmed necrosis in complex with FAS-associated death domain protein (FADD) and cellular FLICE-like inhibitory protein (cFLIP).

  • Many viruses encode inhibitors of caspase 8 activity to suppress apoptosis. Caspase 8 inhibition unveils programmed necrosis, a pathway that may also be suppressed by viral inhibitors of cell death.

  • Programmed necrosis has only recently been recognized as a host-defence pathway through the characterization of cell death suppressors encoded by murine cytomegalovirus (MCMV).

  • Programmed necrosis is dependent on receptor-interacting protein 3 (RIP3) and can be either RIP1-dependent (necroptosis) or RIP1-independent (MCMV-induced programmed necrosis).

  • Pathogen-associated dysregulation of caspase 8 can drive both inflammation and programmed necrosis, contributing to disease outcomes.

Abstract

Pathogens specifically target both the caspase 8-dependent apoptotic cell death pathway and the necrotic cell death pathway that is dependent on receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3). The fundamental co-regulation of these two cell death pathways emerged when the midgestational death of mice deficient in FAS-associated death domain protein (FADD) or caspase 8 was reversed by elimination of RIP1 or RIP3, indicating a far more entwined relationship than previously appreciated. Thus, mammals require caspase 8 activity during embryogenesis to suppress the kinases RIP1 and RIP3 as part of the dialogue between two distinct cell death processes that together fulfil reinforcing roles in the host defence against intracellular pathogens such as herpesviruses.

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Figure 1: Caspase 8-mediated regulation of RIP1–RIP3 signalling pathways.
Figure 2: Viral modulation of cell death signals mediated by caspase 8 activation and RIP1–RIP3 pathways.

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Acknowledgements

The authors thank D. Livingston-Rosanoff and L. Daley-Bauer for their contributions, L. Roback and A. L. McCormick for helping to facilitate this research and C. Benedict for discussions. The research was supported by grants from the US National Institutes of Health (AI030363 and AI020212) and the Georgia Cancer Coalition. We apologize to investigators whose contributions were not cited more extensively owing to space limitations.

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  1. Jason W. Upton and William J. Kaiser: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Emory Vaccine Center, 1462 Clifton Rd. NE, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Edward S. Mocarski & William J. Kaiser

  2. Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, 78712, USA

    Jason W. Upton

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Correspondence to Edward S. Mocarski.

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Glossary

Apoptosis

The most common form of developmental cell death that regulates cell numbers, drives morphogenesis, deletes structures and eliminates unneeded and harmful cells. Apoptosis is a cell-autonomous death pathway mediated by caspases that dismantles the cell but maintains membrane integrity and is characterized by cell shrinkage, membrane blebbing and DNA fragmentation.

RIP1

(Receptor-interacting protein 1; also known as RIPK1). A signalling adaptor and protein kinase that regulates the activation of gene expression via the NF-κB and MAPK pathways and controls the initiation of necroptosis and apoptosis via death domain- and RHIM-dependent complexes.

RIP3

(Receptor-interacting protein 3; also known as RIPK3). A RHIM-containing signalling adaptor and protein kinase that mediates necroptosis and MCMV-induced necrosis.

Programmed necrosis

A cell-autonomous, regulated cell death pathway that is characterized by cell swelling, membrane rupture and cytoplasmic leakage, but not by membrane blebbing.

Necroptosis

A form of programmed necrosis that is executed by the kinase activities of RIP1 and RIP3. This pathway is inhibited by RIP1 kinase inhibitors, such as necrostatin 1 (5-(1H-indol-3-ylmethyl)-3-methyl-2-thioxo-4-imidazolidinone).

RIP homotypic interaction motif

(RHIM). A protein–protein interaction motif containing the core sequence (I/V/L)-(Q/M)-(I/V/L)-G that mediates homophilic interactions between four cellular proteins (namely, RIP1, RIP3, TRIF and DAI) and one viral protein (MCMV vIRA).

Death receptors

A subset of receptors belonging to the TNF receptor superfamily that transmit cell death signals initiated by their cognate ligands. These receptors include TNFR1, FAS, DR3, TRAILR1 and TRAILR2.

Toll-like receptors

(TLRs). A family of pattern recognition receptors that recognize unique structures derived from microorganisms. TLR signalling promotes inflammatory and cytokine responses, as well as cell proliferation or cell death pathways.

FAS

(Also known as CD95). A death receptor of the TNF receptor superfamily. FAS ligand binding induces cell death. FAS signalling controls the homeostatic elimination of T cells.

Death-inducing signalling complex

(DISC). A death receptor-bound complex that contains FADD and caspase 8 (or caspase 10). The DISC assembles following ligand binding and drives autocatalytic caspase 8 (or caspase 10) activation.

Complex I

A TNFR1-bound complex that contains TRADD, TRAF2 or TRAF5, cIAP and RIP1. This complex drives the activation of gene expression via the NF-κB and MAPK pathways.

Cellular inhibitor of apoptosis proteins

(cIAP1 and cIAP2; collectively referred to as cIAP here). Members of a family of functionally and structurally related E3 ubiquitin ligases that regulate canonical and non-canonical activation of NF-κB, as well as MAPK activation by receptors of the TNF receptor superfamily. cIAP polyubiquitylates RIP1 to prevent the formation of the ripoptosome or TNFR1-dependent complex II.

Complex II

A TNFR1- and RIP1-dependent cytosolic complex that contains caspase 8, FADD, cFLIP and RIP1. Within this complex, caspase 8 and cFLIP regulate programmed cell death pathways.

Necrosome

An inducible cytosolic complex that contains oligomerized RIP1 and RIP3. This complex drives RIP1- and RIP3-dependent necroptosis.

Ripoptosome

A RIP1-dependent cytosolic complex that is similar in composition to TNFR1-dependent complex II and that controls programmed cell death pathways.

TIR domain-containing adaptor protein inducing interferon-β

(TRIF). A adaptor protein for TLR3 and TLR4 that organizes downstream signalling cascades leading to IRF3 and NF-κB activation, or cell death. TRIF mediates signalling through a TIR domain, TRAF-binding sites and RHIM-mediated interactions with RIP1 and RIP3.

CARMA1–BCL-10–MALT1 complex

A PKC-dependent specialized signalling complex that is formed during TCR-dependent antigen recognition and that triggers NF-κB activation.

DNA-dependent activator of interferon regulatory factors

(DAI; also known as ZBP1). A cytosolic, RHIM-containing sensor of double-stranded DNA that activates IRF3 and NF-κB.

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Mocarski, E., Upton, J. & Kaiser, W. Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nat Rev Immunol 12, 79–88 (2012). https://doi.org/10.1038/nri3131

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