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- Title
A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.
- Authors
Kung, G; Dai, P; Deng, L; Kitsis, R N
- 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.
- Subjects
APOPTOSIS inhibition; TUMOR necrosis factor receptors; NECROSIS; DEATH receptors; CASPASES regulation
- Publication
Cell Death & Differentiation, 2014, Vol 21, Issue 4, p634
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/cdd.2013.195