Reactome | Caspase-8 and FLIP(L) processing at DISC

Caspase-8 and FLIP(L) processing at DISC

Stable Identifier

R-HSA-3465448

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Caspase-8 and FLIP(L) processing at DISC

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In the presence of FLIP(L), both caspase-8 and FLIP(L) are recruited and partially processed at the death-inducing signaling complex (DISC). The partially processed proteins stay bound to the DISC.

The long cellular FLIP (FLIP(L) or c-FLIPL) has two death effector domains (DED) and a caspase-like domain that lacks catalytic activity due to absence of a cysteine residue. Processing of FLIP(L) occurs at the DISC and depends on caspase-8 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; Jong WY et al. 2009). Processed FLIP(L) can enhance the proteolytic activity of procaspase-8 (Chang DW et al. 2002; Jong WY et al. 2009; Pop C et al. 2011). However, the increased FLIP(L) protein levels in cells have been found to limit caspase-8 activity and inhibit apoptotic signaling pathway,

Literature References

PubMed ID	Title	Journal	Year
19278658	Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation Keller, N, Mares, J, Zerbe, O, Grütter, MG	Structure	2009
19416807	Mechanism of procaspase-8 activation by c-FLIPL Yu, JW, Jeffrey, PD, Shi, Y	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 Pop, C, Oberst, A, Drag, M, Van Raam, BJ, Riedl, SJ, Green, DR, Salvesen, GS	Biochem J	2011
20696707	Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL Fricker, N, Beaudouin, J, Richter, P, Eils, R, Krammer, PH, Lavrik, IN	J. Cell Biol.	2010
10837247	The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways Kataoka, T, Budd, RC, Holler, N, Thome, M, Martinon, F, Irmler, M, Burns, K, Hahne, M, Kennedy, N, Kovacsovics, M, Tschopp, J	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