DAI complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA

By J. Upton, William J. Kaiser, E. Mocarski. Cell Host and Microbe, 2012

721 citations recorded by the source corpus.

Summary Programmed necrosis, like apoptosis, eliminates pathogen infected cells as a component of host defense. Receptor interacting protein kinase (RIP) 3 (also called RIPK3) mediates programmed necrosis via RIP homotypic interaction motif (RHIM)-dependent interactions, which is induced by murine cytomegalovirus (MCMV) infection or death receptor activation and is suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI; also known as ZBP1 or DLM-1), sensitizes cells to virus-induced necrosis and DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3−/− mice, vIRA mutant MCMV pathogenesis is restored in DAI−/− mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4a89810fc23b019610232298ccbc4b4abf2a3627

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Citations in the corpus

Cell Death Signaling. (2015, background): “DAI is activated by double-stranded viral DNA and recruits RIP3 through its RHIM domain (Upton et al. 2012).”
ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “ZBP1 is one of the RIP homotypic interaction motif (RHIM)containing proteins and is known to activate necroptosis via RIPK3, another RHIM-containing protein (Rebsamen et al., 2009; Upton et al., 2012; Kuriakose and Kanneganti, 2018).”
Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “vIRA, amolecule expressed by MCMV that contains a RHIM-like domain blocks RIPK3 recruitment to RIPK1 and to DAI (57).”
Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “Rather, at least two other proteins can physically interact with RIPK3 through a bona fide RHIM and hence drive necroptosis, namely Z-DNA binding protein 1 (ZBP1; also known as DAI) (93, 94) and toll-like receptor adaptor molecule 1 (TICAM1; best known as TRIF) (95).”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “Similarly, RHIM-mediated interaction between the intracellular DNAsensorDAI andRIP3 causesnecrosis of cells infected with murine cytomegalovirus (Upton et al., 2012).”