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Cell Death Differ. 2014 Apr;21(4):634-44. doi: 10.1038/cdd.2013.195. Epub 2014 Jan 17.

A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.

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Departments of Cell Biology and Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.


TNFα signaling can promote apoptosis or a regulated form of necrosis. ARC (apoptosis repressor with CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that antagonizes both the extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways. We discovered that ARC blocks not only apoptosis but also necrosis. TNFα-induced necrosis was abrogated by overexpression of wild-type ARC but not by a CARD mutant that is also defective for inhibition of apoptosis. Conversely, knockdown of ARC exacerbated TNFα-induced necrosis, an effect that was rescued by reconstitution with wild-type, but not CARD-defective, ARC. Similarly, depletion of ARC in vivo exacerbated necrosis caused by infection with vaccinia virus, which elicits severe tissue damage through this pathway, and sensitized mice to TNFα-induced systemic inflammatory response syndrome. The mechanism underlying these effects is an interaction of ARC with TNF receptor 1 that interferes with recruitment of RIP1, a critical mediator of TNFα-induced regulated necrosis. These findings extend the role of ARC from an apoptosis inhibitor to a regulator of the TNFα pathway and an inhibitor of TNFα-mediated regulated necrosis.

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