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.
Yu, JW, Jeffrey, PD, Shi, Y
Keller, N, Mares, J, Zerbe, O, Grütter, MG
Pop, C, Oberst, A, Drag, M, Van Raam, BJ, Riedl, SJ, Green, DR, Salvesen, GS
Kataoka, T, Budd, RC, Holler, N, Thome, M, Martinon, F, Irmler, M, Burns, K, Hahne, M, Kennedy, N, Kovacsovics, M, Tschopp, J
Kataoka, T, Tschopp, J
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