The roles of FADD in extrinsic apoptosis and necroptosis

Eun-Woo Lee, Jin-Ho Seo, Man-Hyung Jeong, Sang-Sik Lee, Jae-Whan Song
2012 BMB Reports  
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
more » ... es 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] EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosis Extrinsic apoptosis, which is triggered by the extracellular signals that activate the death receptor family, is distinguished from intrinsic apoptosis, which is induced by intracellular signals such as DNA damage, oxidative stress, and nutrient deprivation (23). Extrinsic apoptosis is initiated by the binding of specific ligands such as tumor necrosis factor α (TNFα), Fas ligand (FasL), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to their corresponding receptors called 'death receptors' (DRs) (24). DR is a member of the TNF receptor superfamily and specifically contains a conserved cytosolic death domain (DD) (25). The eight kinds of DRs have different amino acid sequences that determine ligand specificity, and they can be divided into two groups according to the cytosolic adaptor protein that makes a distinct complex (24, 26, 27) . The first group includes CD95/Fas, DR4/TRAIL-R1, and DR5/ TRAIL-R2, all of which recruit death-inducing signaling complex (DISC) composed of FADD and procaspase-8 (28). Fas and DR4/5 are activated by the ligation of the specific ligands FasL and TRAIL, respectively, and bind to the DD of FADD, a pivotal adaptor protein, through the DD domain. Then, DED of FADD binds to DED of procaspase-8 and -10 to construct the DISC. The
doi:10.5483/bmbrep.2012.45.9.186 pmid:23010170 fatcat:bovppcyfnrbhfbyq4jzz7zkstm