Cell death triggered by extrinsic stimuli via death receptors or toll-like receptors (e.g., TLR3, TLR4) may result in either apoptosis or regulated necrosis (necroptosis) (Holler N et al. 2000; Kalai M et al. 2002; Kaiser WJ and Offermann MK 2005; Yang P et al. 2007). Caspase-8 (CASP8) is a cysteine protease, which functions as a key mediator for determining which form of cell death will occur (Kalai M et al. 2002). The proteolytic activity of a fully processed, heterotetrameric form of CASP8 in human and rodent cells is required for proapoptotic signaling and also for a cleavage of kinases RIPK1 and RIPK3, while at the same time preventing RIPK1/RIPK3-dependent regulated necrosis (Juo P et al. 1998; Lin Y et al. 1999; Holler N et al. 2000; Hopkins-Donaldson S et al. 2000). A blockage of CASP8 activity in the presence of caspase inhibitors such as Z-VAD-FMK (pan-caspase inhibitor), endogenous FLIP(S) or viral FLIP-like protein was found to switch signaling to necrotic cell death (Thome M et al. 1997; Kalai M et al. 2002; Feoktistova M et al. 2011; Sawai H 2013).
Kalai, M, Van Loo, G, Vandenabeele, P, Burm, W, Meeus, A, Vanden Berghe, T, Saelens, X
Sawai, H
Hofmann, K, Krammer, PH, Neipel, F, Meinl, E, Schröter, M, Tschopp, J, Scaffidi, C, Bodmer, JL, Peter, ME, Schneider, P, Thome, M, Mattmann, C, Burns, K, Fickenscher, H
Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP
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