Virus Inhibition of RIP3-Dependent Necrosis

Abstract

Summary Viral pathogenesis relies upon modulation of host cytokine activation as well as cell death pathways. Infection by murine cytomegalovirus induces a novel receptor-interacting protein (RIP)3-dependent necrosis. RIP3 kinase activity and homotypic interaction motif (RHIM)-dependent interactions control virus-associated necrosis as occurs in TNFα-induced necroptosis; however, the virus-induced death pathway proceeds independent of RIP1, and is therefore distinct from the TNFα-dependent death pathway. The viral inhibitor of RIP activation (vIRA, encoded by the viral M45 gene) suppresses either pathway, disrupting RHIM-dependent RIP3-RIP1 interaction that is critical for TNFα-induced necroptosis as well as a RIP3 RHIM-dependent step in virus-induced necrosis. Importantly, the attenuation of vIRA-deficient virus in wild type mice is completely normalized in a RIP3-deficient genetic background. Thus, vIRA function validates necrosis as central to the elimination of infected cells in host defense and highlights the benefit of multiple virus-encoded cell death suppressors that subvert not only apoptotic, but also necrotic mechanisms of virus clearance.

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

“…26 Cytomegalovirus has also been demonstrated to avoid immune activation by inhibiting Rip3 as a key survival mechanism. 43 In contrast to this role, our data show that overactive necroptosis impairs immune control of a bacterial infection. Specifically, lower expression of cIAP in vivo resulted in significantly elevated macrophage death and bacterial burden.…”

Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

“…Furthermore, cytomegalovirus encodes caspase inhibitors and vIRA, which disrupts the host RHIM-dependent RIPK1 and RIPK3 interaction to promote pathogenesis. 10 However, the role of necroptosis as an anti-viral strategy appears to be more complex and context dependent than initially presumed. Previous studies using poxviruses that encode caspase inhibitors have shown that virus deficient in cytokine response modifier A (CrmA), a potent Caspase-1 and -8 inhibitor, is less pathogenic than wild-type virus capable of inducing necroptosis and processing IL-1β.…”

“…[6][7][8] Necroptosis is generally viewed as a pro-inflammatory mode of cell death, and many studies have concluded that this represents a host response to viral infection that limits viral replication. [9][10][11] However, it is frequently overlooked that the majority of TNF-responsive cell types do not undergo apoptosis, or indeed necrosis, in response to TNFR engagement. Instead, most cells initiate highly robust nuclear factor kappa B (NFκB)-dependent pro-inflammatory responses upon stimulation with this cytokine.…”

RIP kinases: key decision makers in cell death and innate immunity

“…115 Intriguingly, MCMV encodes a M45 protein, that also contains a RHIM and targets the DAI-RIP3 interaction to suppress premature killing of endothelial cells during MCMV infection. 116,117 Such findings highlight the importance of RIPmediated necroptosis to anti-viral immunity. 6,118 The RNA helicase RIG-I also serves as a cytoplasmic viral sensor by recognizing viral RNA.…”