RIPK1 is cleaved by CASP8:FLIP(L)

Stable Identifier
Reaction [omitted]
Homo sapiens
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Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can be a part of cell death and survival signaling complexes. Whether RIPK1 functions in apoptosis, necroptosis or NFkB signaling is dependent on autocrine/paracrine signals, on the cellular context and tightly regulated by posttranslational modifications of RIP1 itself. Following ligation of TNFR1, RIPK1 is recruited to the TNFR1:TRADD:TRAF2 complex where it is ubiquitinated by BIRC2/3 (also known as inhibitor of apoptosis proteins cIAP1/2) and LUBAC. Polyubiquitination of RIPK1 is required for recruitment of signaling molecules/complexes such as the IKK complex and TAK1 complex. IKKs and TAK1 phosphorylate RIPK1 to limit its cytotoxic activity and activate NFkappaB and MAPK pathways, resulting in expression of both pro-inflammatory cytokines and pro-survival genes including FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein (cFLIP, encoded by the CFLAR gene) (Ea CK et al. 2006). Conversely, deubiquitination of RIPK1, mediated by BIRC2/3 (cIAP) inhibition or the deubiquitylases A20 or CYLD, switches the pro-survival function of RIPK1 to caspase-mediated pro-apoptotic signaling (Fujikura D et al. 2012; Moquin DM et al. 2013). The TRADD:TRAF2:RIPK1 complex detaches from TNFR1 and recruits FADD and procaspase-8 (CASP8). CASP8 in human and rodent cells facilitates the cleavage of kinases RIPK1 and RIPK3 and prevents RIPK1/RIPK3-dependent necroptosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000; Meng H et al. 2018; Newton K et al. 2019; Zhang X et al. 2019; Tao P et al. 2020; Lalaoui N et al. 2020). The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of CASP8 and cFLIP (CFLAR) (reviewed in Tummers B & Green DR 2017). In the presence of cFLIP, both CASP8 and FLIP are recruited to the TRADD:TRAF2:RIPK1:FADD complex. cFLIP exists in two main isoforms: long FLIP(L) and short FLIP(S) forms. 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). 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). Note that the latest statement has been proven in the context of the TLR3 signalling pathway.

Literature References
PubMed ID Title Journal Year
19416807 Mechanism of procaspase-8 activation by c-FLIPL

Shi, Y, Jeffrey, PD, Yu, JW

Proc. Natl. Acad. Sci. U.S.A. 2009
Catalyst Activity

cysteine-type endopeptidase activity of TRADD:TRAF2:RIPK1:FADD:p43/p41CASP8:p43 FLIP(L) [plasma membrane]

Orthologous Events
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