Research ArticleCell Biology

c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis

Sci. Signal.  18 Dec 2012:
Vol. 5, Issue 255, pp. ra93
DOI: 10.1126/scisignal.2003558

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FLIPping Multiple Death Signals Off

The gene c-Flip, which encodes the antiapoptotic protein c-FLIP, is expressed in response to nuclear factor κB (NF-κB) activation. NF-κB–mediated protection of the intestine and liver from proapoptotic signaling is important for tissue maintenance (homeostasis). Avoiding the embryonic lethality caused by complete knockout of c-Flip in mice, Piao et al. selectively deleted c-Flip in intestinal epithelial cells (IECs) or hepatocytes. Whereas c-FLIP–deficient IECs exhibited tumor necrosis factor (TNF)–dependent apoptosis and programmed necrosis, a cell death process morphologically and mechanistically distinct from that of apoptosis, leading to perinatal death of the mice, c-FLIP–deficient hepatocytes exhibited apoptosis and programmed necrosis, and mice died in a TNF-independent manner. Induced loss of c-FLIP in hepatocytes in adult mice led to lethal hepatitis, which was prevented by blocking multiple proinflammatory factors that trigger apoptosis. Together, these data show that c-FLIP blocks both apoptosis and programmed necrosis to maintain tissue homeostasis and suggest that targeting both cell death pathways may be effective in treating certain viral infections in which c-FLIP abundance is reduced.