A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.
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.
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.
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Kung
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Dai
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Deng
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.
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Kitsis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D024243:HMGB1 Protein; D009124:Muscle Proteins; D016328:NF-kappa B; C491787:Nol3 protein, mouse; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha