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

G. Kung, P. Dai, L. Deng, Richard N. Kitsis

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalCell Death and Differentiation
Volume21
Issue number4
DOIs
StatePublished - Apr 2014

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AIDS-Related Complex
Necrosis
Apoptosis
Systemic Inflammatory Response Syndrome
Death Domain Receptors
Vaccinia virus
Tumor Necrosis Factor Receptors

Keywords

  • apoptosis
  • ARC
  • necrosis
  • TNFα

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis. / Kung, G.; Dai, P.; Deng, L.; Kitsis, Richard N.

In: Cell Death and Differentiation, Vol. 21, No. 4, 04.2014, p. 634-644.

Research output: Contribution to journalArticle

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