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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.

Author information

1
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.
2
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Abstract

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.

PMID:
24440909
PMCID:
PMC3950326
DOI:
10.1038/cdd.2013.195
[Indexed for MEDLINE]
Free PMC Article

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