Reactome | FLIP(L) and procaspase-8 form heterodimer

FLIP(L) and procaspase-8 form heterodimer

Stable Identifier

R-HSA-5675456

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

FLIP(L) and procaspase-8 form heterodimer

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

The balance between caspase-dependent apoptosis and RIPK-dependent necroptosis was found to depend on the levels of caspase-8 (CASP8) and cellular FADD-like interleukin-1 beta converting enzyme (FLICE)-inhibitory protein (cFLIP, encoded by the CFLAR gene) (Feoktistova M et al. 2011; Hughes MA et al. 2016; 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) form heterodimers with procaspase-8, however they differentially regulate CASP8 activation (Feoktistova M et al. 2011; Dillon CP et al. 2012). The pseudoprotease FLIP(L) interacts with procaspase-8 through both death effector domains (DED) and caspase-like domain (CLD) that lacks catalytic activity due to absence of a cysteine residue in FLIP(L). The procaspase-8 catalytic domain prefers heterodimerization with the CLD of FLIP(L) over homodimerization with catalytic domains of other procaspase-8 molecules (Boatright KM et al. 2004; Yu JW et al. 2009). Heterodimerization to FLIP(L) rearranges the catalytic site of procaspase-8, producing a conformation that renders the heterodimer highly active even in the absence of proteolytic processing of either caspase-8 or cFLIPL (Micheau O et al. 2002; Yu JW et al. 2009; reviewed in Tummers B & Green DR 2017). The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011; Hughes MA et al. 2016). When FLIP(L) is expressed at high levels, the enzymatic activity of the FLIP(L):CASP8 heterodimer with procaspase-8 being an active unit is insufficient to generate active CASP8 heterotetramers for the apoptosis induction in mammalian cells. In contrary, the residual catalytic activity of FLIP(L):CASP8 is sufficient for RIPK1/RIPK3 cleavage, which inhibited the necroptotic cell death mode (Feoktistova M et al. 2011; Dillon CP et al. 2012; Oberst A et al. 2011).

Literature References

PubMed ID	Title	Journal	Year
9880531	The role of c-FLIP in modulation of CD95-induced apoptosis Krammer, PH, Peter, ME, Schmitz, I, Scaffidi, C	J. Biol. Chem.	1999
11463813	NF-kappaB signals induce the expression of c-FLIP Gaide, O, Micheau, O, Tschopp, J, Lens, S, Alevizopoulos, K	Mol. Cell. Biol.	2001
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
21737330	cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP	Mol. Cell	2011