A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis Journal Article
| Authors: | Kung, G.; Dai, P.; Deng, L.; Kitsis, R. N. |
| Article Title: | A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis |
| 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. © 2014 Macmillan Publishers Limited All rights reserved. |
| Keywords: | nonhuman; animal cell; mouse; mus; apoptosis; enzyme inhibition; protein depletion; animal experiment; in vivo study; in vitro study; necrosis; tumor necrosis factor alpha; vaccinia virus; virus infection; gene silencing; animal cell culture; tissue injury; arc; systemic inflammatory response syndrome; necroptosis; priority journal; article; tnfα; apoptosis repressor with caspase recruitment domain |
| Journal Title: | Cell Death and Differentiation |
| Volume: | 21 |
| Issue: | 4 |
| ISSN: | 1350-9047 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2014-01-01 |
| Start Page: | 634 |
| End Page: | 644 |
| Language: | English |
| DOI: | 10.1038/cdd.2013.195 |
| PROVIDER: | scopus |
| PMCID: | PMC3950326 |
| PUBMED: | 24440909 |
| DOI/URL: | |
| Notes: | Export Date: 1 August 2014 -- CODEN: CDDIE -- Source: Scopus |
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