| First Author | Kung G | Year | 2014 |
| Journal | Cell Death Differ | Volume | 21 |
| Issue | 4 | Pages | 634-44 |
| PubMed ID | 24440909 | Mgi Jnum | J:218360 |
| Mgi Id | MGI:5617337 | Doi | 10.1038/cdd.2013.195 |
| Citation | Kung G, et al. (2014) A novel role for the apoptosis inhibitor ARC in suppressing TNFalpha-induced regulated necrosis. Cell Death Differ 21(4):634-44 |
| abstractText | TNFalpha 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. TNFalpha-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 TNFalpha-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 TNFalpha-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 TNFalpha-induced regulated necrosis. These findings extend the role of ARC from an apoptosis inhibitor to a regulator of the TNFalpha pathway and an inhibitor of TNFalpha-mediated regulated necrosis. |
