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. Author manuscript; available in PMC: 2015 Jul 27.
Published in final edited form as: Nat Rev Immunol. 2011 Dec 23;12(2):79–88. doi: 10.1038/nri3131

Figure 2. Viral modulation of cell death signals mediated by caspase 8 activation and RIP1–RIP3 pathways.

Figure 2

a ∣ Viral proteins that directly target receptor-interacting protein 1 (RIP1), FAS-associated death domain protein (FADD) and/or caspase 8 suppress signalling pathways that are activated by death receptors, pattern recognition receptors (PRRs; such as Toll-like receptor 3 (TLR3)) or cell stress (such as DNA damage). Many virus-encoded proteins block caspase 8-dependent apoptosis by interfering with caspase 8, FADD and/or RIP1 (see also TABLE 1). Several poxvirus proteins of the serpin family bind directly to fully processed caspase 8 to prevent apoptosis, whereas other viral inhibitors of caspase 8 — such as vICA (viral inhibitor of caspase 8 activation), CrmA and B13R (all highlighted in blue) — sensitize cells to death receptor-induced necroptosis by disrupting caspase 8-mediated suppression of RIP1–RIP3 activity. A subset of viral FLICE-like inhibitory proteins (vFLIPs) — including MC159, E8 and the murine cytomegalovirus (MCMV) protein vIRA (viral inhibitor of RIP activation) — block both apoptosis and RIP1- and RIP3-mediated necrosis. b ∣ The MCMV protein vICA prevents caspase 8 activation, and this sensitizes cells to death receptor-induced necroptosis. In addition, the MCMV protein vIRA blocks necroptosis and MCMV-induced programmed necrosis by inhibiting RHIM (RIP homotypic interaction motif)-dependent interactions. vIRA also inhibits the activation of caspase 8 by RIP1 or TIR domain-containing adaptor protein inducing IFNβ (TRIF). c ∣ A mutant MCMV that encodes vIRA with a mutant RHIM domain triggers programmed necrosis in cells with sufficient levels of RIP3. MCMV-induced programmed necrosis is independent of RIP1. The cellular RHIM-containing cytosolic sensor of double-stranded DNA DAI (DNA-dependent activator of interferon regulatory factors) may promote RIP3-dependent programmed necrosis during infection with mutant MCMV. Stars indicate catalytically active caspase 8. BHV-4, bovine herpesvirus 4; DED, death effector domain; EHV-1, equine herpesvirus 1; HCMV, human cytomegalovirus; HPV-16, human papillomavirus 16; HSV, herpes simplex virus; HVS, herpesvirus saimiri; KSHV, Kaposi’s sarcoma-associated herpesvirus; MCV, molluscum contagiosum virus.