CASP8 activity is inhibited

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Homo sapiens
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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 peptidase, 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).?

Literature References
PubMed ID Title Journal Year
23410748 Differential effects of caspase inhibitors on TNF-induced necroptosis

Sawai, H

Biochem. Biophys. Res. Commun. 2013
12181749 Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

Kalai, M, Van Loo, G, Vanden Berghe, T, Meeus, A, Burm, W, Saelens, X, Vandenabeele, P

Cell Death Differ. 2002
9087414 Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors

Thome, M, Schneider, P, Hofmann, K, Fickenscher, H, Meinl, E, Neipel, F, Mattmann, C, Burns, K, Bodmer, JL, Schröter, M, Scaffidi, C, Krammer, PH, Peter, ME, Tschopp, J

Nature 1997
21737330 cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms

Feoktistova, M, Geserick, P, Kellert, B, Dimitrova, DP, Langlais, C, Hupe, M, Cain, K, MacFarlane, M, Häcker, G, Leverkus, M

Mol. Cell 2011
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