TY - JOUR
T1 - DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA
AU - Upton, Jason W.
AU - Kaiser, William J.
AU - Mocarski, Edward S.
N1 - Funding Information:
We thank Ken Ishii (NIBIO) and Shizuo Akira (Osaka University) for DAI −/− mice, Vishva Dixit and Kim Newton (Genentech) for RIP3 −/− mice, David Lembo (University of Turin) for anti-M45 antibody, and Tilmann Bürckstümmer and Giulio Superti-Furga (CeMM) for anti-DAI antibody. This work was supported by the National Institutes of Health (NIH) (PHS grants R01 AI20211 and AI30363 to E.S.M. and F32 AI080175-01A1 to J.W.U.).
PY - 2012/3/15
Y1 - 2012/3/15
N2 - Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and 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 that 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.
AB - Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and 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 that 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.
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U2 - 10.1016/j.chom.2012.01.016
DO - 10.1016/j.chom.2012.01.016
M3 - Article
C2 - 22423968
AN - SCOPUS:84858420051
SN - 1931-3128
VL - 11
SP - 290
EP - 297
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -