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

• Type of Material: Article
• Authors: Jason W. Upton, Emory University; William J. Kaiser, Emory University; Edward S Mocarski, Emory University
• Language: English
• Date: 2012-03-15
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chom.2012.01.016
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 11
• Issue: 3
• Start Page: 290
• End Page: 297
• Grant/Funding Information: This work was supported by the NIH (PHS grants R01 AI20211 and AI30363 to E.S.M. and F32 AI080175-01A1 to J.W.U.).
• Research Categories: Biology, Microbiology

Abstract

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.