The roles of FADD in extrinsic apoptosis and necroptosis

Abstract

Fas-associated protein with death domain (FADD), an adaptor that bridges death receptor signaling to the caspase cascade, is indispensible for the induction of extrinsic apoptotic cell death. Interest in the non-apoptotic function of FADD has greatly increased due to evidence that FADD-deficient mice or dominant-negative FADD transgenic mice result in embryonic lethality and an immune defect without showing apoptotic features. Numerous studies have suggested that FADD regulates cell cycle progression, proliferation, and autophagy, affecting these phenomena. Recently, programmed necrosis, also called necroptosis, was shown to be a key mechanism that induces embryonic lethality and an immune defect. Supporting these findings, FADD was shown to be involved in various necroptosis models. In this review, we summarize the mechanism of extrinsic apoptosis and necroptosis, and discuss the in vivo and in vitro roles of FADD in necroptosis induced by various stimuli.[BMB Reports 2012; 45(9): 496-508] INTRODUCTIONFas-associated protein with death domain (FADD) is a critical adaptor protein for death receptor (DR)-mediated apoptosis. FADD is composed of two domains called the death domain (DD) and death effector domain (DED). The DD of FADD binds to the DD of the death receptor and FADD recruits procaspase-8 through the DED-DED interaction, forming a death-inducing signaling complex (DISC), where procaspase-8 is activated by self-cleavage. Active caspase-8 cleaves downstream effector caspases such as caspase-3, -6, and -7, inducing apoptosis. Interestingly, FADD deficiency results in embryonic lethality, displaying a defect in immune homeostasis and immune cell proliferation despite the defect in inducing apoptosis. In addition, FADD is also implicated in non-apoptotic functions such as cell cycle progression, proliferation, autophagy, inflammation and innate immunity (1, 2). Particularly, FADD phosphorylation at Ser194 (pFADD) by several kinases is associated with its nuclear localization and cell cycle regulation (3-8). Although FADD and pFADD are often overexpressed in various tumors, their functions in cancer development or chemotherapy-sensitivity are still controversial (9-14). Recent strong evidence from in vivo mice studies suggested negative roles of FADD in RIP1-and RIP3-dependent necroptosis (15-18). DR-mediated caspase-8 activation requires FADD, and leads to the cleavage of RIP1, RIP3, and CYLD, preventing necroptosis (19)(20)(21)(22). Thus, FADD deficiency is thought to inhibit caspase-8 and subsequent apoptosis, but activate necroptosis. Since necroptosis can be initiated by various stimuli in a variety of cell types independently of DRs, the exact mechanisms and functions of FADD require further investigation. This review focuses on the recent discoveries about the roles of FADD in apoptosis and necroptosis in various models, and we refer the reader to two comprehensive reviews of the diverse functions of FADD (1, 2). EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosisExtrinsic apoptosis, which is...

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