N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway
Details
Serval ID
serval:BIB_6B2DFE888CED
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway
Journal
Molecular and Cellular Biology
ISSN
0270-7306 (Print)
Publication state
Published
Issued date
04/2004
Volume
24
Number
7
Pages
2627-36
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Apr
Research Support, Non-U.S. Gov't --- Old month value: Apr
Abstract
Caspase 8 is required not only for death receptor-mediated apoptosis but also for lymphocyte activation in the immune system. FLIP(L), the long-splice form of c-FLIP, is one of the specific substrates for caspase 8, and increased expression of FLIP(L) promotes activation of the NF-kappaB signaling pathway. The synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) markedly blocked NF-kappaB activation induced by overexpression of FLIP(L). FLIP(L) is specifically processed by caspase 8 into N-terminal FLIP(p43) and C-terminal FLIP(p12). Only FLIP(p43) was able to induce NF-kappaB activation as efficiently as FLIP(L), and FLIP(p43)-induced NF-kappaB activation became insensitive to zVAD-fmk. In caspase 8-deficient cells, FLIP(p43) provoked NF-kappaB activation only when procaspase 8 or caspase 8(p43) was complemented. FLIP(p43)-induced NF-kappaB activation was profoundly blocked by the dominant-negative TRAF2. Moreover, endogenous TRAF2 interacted specifically with FLIP(p43), and the formation of the FLIP(p43)-caspase 8-TRAF2 tertiary complex was a prerequisite to induction of NF-kappaB activation. zVAD-fmk prevented the recruitment of TRAF2 into the death-inducing signaling complex. Thus, our present results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts with TRAF2 and subsequently induces activation of the NF-kappaB signaling pathway.
Keywords
Amino Acid Chloromethyl Ketones/metabolism
Animals
CASP8 and FADD-Like Apoptosis Regulating Protein
Carrier Proteins/genetics/*metabolism
Caspase 8
Caspases/*metabolism
Cell Line
Dimerization
Enzyme Activation
Enzyme Inhibitors/*metabolism
Humans
*Intracellular Signaling Peptides and Proteins
Mice
NF-kappa B/*metabolism
Peptide Fragments/genetics/*metabolism
Proteins/*metabolism
Signal Transduction/*physiology
TNF Receptor-Associated Factor 2
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 16:19
Last modification date
20/08/2019 15:25