Caspase-8 and FLIP(L) processing at TNFR signaling complex

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Reaction [omitted]
Homo sapiens
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The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein isoforms (cFLIP, encoded by the CFLAR gene) (reviewed in Tummers B & Green DR 2017). cFLIP exists in two main isoforms: long FLIP(L) and short FLIP(S) forms. Both FLIP(L) and FLIP(S) dimerize with procaspase-8 at the death‑inducing signaling complex (DISC) such as TRADD:TRAF2:RIPK1: FADD:CASP8:FLIP(L), however they differentially regulate CASP8 activation (Pop C et al. 2011; Oberst A et al. 2011; Hughes MA et al. 2009, 2016). The heterodimers of FLIP(L):CASP8 inhibit CASP8 activity limiting the cleavage of CASP3/7 but allowing the cleavage of RIPK1 to cause the dissociation of the TRADD:TRAF2:RIPK1:FADD:CASP8 complex, thereby inhibiting both apoptosis and necroptosis (Pop C et al. 2011; Oberst A et al. 2011; Hughes MA et al. 2009; Lalaoui N et al 2020). Processing of FLIP(L) also occurs at the DISC and depends on CASP8 activity (zymogen and mature form). Upon activation FLIP(L) is cleaved to generate N‑terminal FLIP(p43) and C‑terminal FLIP(p12) (Irmler M et al. 1997; Chang DW et al. 2002; Yu JW et al. 2009; Pop C et al. 2011). FLIP(S) is a truncated version of procaspase‑8 containing tandem DEDs only. FLIP(S) acts purely as an antagonist of CASP8 activity inhibiting apoptosis. FLIP(S) has also been proposed to induce necroptosis in conditions when RIPK1 is deubiquitylated and when FLIP(L) is absent (Feoktistova M et al. 2011). Important to note that the latest statement has been shown in the context of the TLR3 signalling pathway.
Literature References
PubMed ID Title Journal Year
19278658 Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation

Zerbe, O, Keller, N, Grütter, MG, Mares, J

Structure 2009
19416807 Mechanism of procaspase-8 activation by c-FLIPL

Shi, Y, Jeffrey, PD, Yu, JW

Proc. Natl. Acad. Sci. U.S.A. 2009
21235526 FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity

Drag, M, Van Raam, BJ, Oberst, A, Green, DR, Riedl, SJ, Salvesen, GS, Pop, C

Biochem J 2011
10837247 The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways

Hahne, M, Irmler, M, Budd, RC, Martinon, F, Thome, M, Kovacsovics, M, Kataoka, T, Tschopp, J, Burns, K, Holler, N, Kennedy, N

Curr. Biol. 2000
15024054 N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway

Kataoka, T, Tschopp, J

Mol. Cell. Biol. 2004
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