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Review
. 2017 May;277(1):90-101.
doi: 10.1111/imr.12539.

RIPK3-driven cell death during virus infections

Jason W Upton  1 , Maria Shubina  2 , Siddharth Balachandran  2
Affiliations
Review

RIPK3-driven cell death during virus infections

Jason W Upton et al. Immunol Rev. 2017 May.

Abstract

The programmed self-destruction of infected cells is a powerful antimicrobial strategy in metazoans. For decades, apoptosis represented the dominant mechanism by which the virus-infected cell was thought to undergo programmed cell death. More recently, however, new mechanisms of cell death have been described that are also key to host defense. One such mechanism in vertebrates is programmed necrosis, or "necroptosis", driven by receptor-interacting protein kinase 3 (RIPK3). Once activated by innate immune stimuli, including virus infections, RIPK3 phosphorylates the mixed lineage kinase domain-like protein (MLKL), which then disrupts cellular membranes to effect necroptosis. Emerging evidence demonstrates that RIPK3 can also mediate apoptosis and regulate inflammasomes. Here, we review studies on the mechanisms by which viruses activate RIPK3 and the pathways engaged by RIPK3 that drive cell death.

Keywords: RIPK1; RIPK3; apoptosis; necroptosis; necrosis; viruses.

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Figures

Figure 1.
Figure 1.. RIPK3-driven cell death during virus infections.
Multiple viruses activate RIPK3 by different upstream mechanisms during their life cycles, leading to phosphorylation of MLKL and necroptosis, as well as recruitment of FADD and caspase-8-mediated apoptosis. The survival advantage to the virus of blocking RIPK3 signaling is highlighted by the growing number of virus proteins that target activation of these pathways during species-specific co-evolution of viruses with their natural hosts. Activation or inhibition of RIPK3 signaling is often mediated by RHIM-based homotypic interactions; the RHIM in proteins containing this motif is shown as a red rectangle. (HSV, herpes simplex virus; MCMV, murine cytomegalovirus; IAV, influenza A virus; VV, vaccinia virus.)
Figure 2.
Figure 2.. RHIM containing proteins.
Four vertebrate proteins (DAI, RIPK1, RIPK3, and TRIF) and three virus proteins (MCMV vIRA, HSV-1 ICP6, and HSV-2 ICP10) have known RHIMs. Amino acid lengths are for murine orthologs of each protein, where relevant.
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