A novel role for the apoptosis inhibitor ARC in suppressing TNF alpha-induced regulated necrosis

作者：Kung G; Dai P; Deng L; Kitsis R N^*

来源：Cell Death and Differentiation, 2014, 21(4): 634-644.

DOI：10.1038/cdd.2013.195

• ARC
• necrosis
• apoptosis
• TNF alpha

TNF alpha 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. TNF alpha-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 TNF alpha-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 TNF alpha-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 TNF alpha-induced regulated necrosis. These findings extend the role of ARC from an apoptosis inhibitor to a regulator of the TNF alpha pathway and an inhibitor of TNF alpha-mediated regulated necrosis.

• 出版日期2014-4