Cellular FLICE-inhibitory Protein (cFLIP) Isoforms Block CD95- and TRAIL Death Receptor-induced Gene Induction Irrespective of Processing of Caspase-8 or cFLIP in the Death-inducing Signaling Complex
Open accessAbstract
Death receptors (DRs) induce apoptosis but also stimulate proinflammatory "non-apoptotic" signaling (e.g. NF-κB and mitogen-activated protein kinase (MAPK) activation) and inhibit distinct steps of DR-activated maturation of procaspase-8. To examine whether isoforms of cellular FLIP (cFLIP) or its cleavage products differentially regulate DR signaling, we established HaCaT cells expressing cFLIP(S), cFLIP(L), or mutants of cFLIP(L) (cFLIP(D376N) and cFLIP(p43)). cFLIP variants blocked TRAIL- and CD95L-induced apoptosis, but the cleavage pattern of caspase-8 in the death inducing signaling complex was different: cFLIP(L) induced processing of caspase-8 to the p43/41 fragments irrespective of cFLIP cleavage. cFLIP(S) or cFLIP(p43) blocked procaspase-8 cleavage. Analyzing non-apoptotic signaling pathways, we found that TRAIL and CD95L activate JNK and p38 within 15 min. cFLIP variants and different caspase inhibitors blocked late death ligand-induced JNK or p38 MAPK activation suggesting that these responses are secondary to cell death. cFLIP isoforms/mutants also blocked death ligand-mediated gene induction of CXCL-8 (IL-8). Knockdown of caspase-8 fully suppressed apoptotic and non-apoptotic signaling. Knockdown of cFLIP isoforms in primary human keratinocytes enhanced CD95L- and TRAIL-induced NF-κB activation, and JNK and p38 activation, underscoring the regulatory role of cFLIP for these DR-mediated signals. Whereas the presence of caspase-8 is critical for apoptotic and non-apoptotic signaling, cFLIP isoforms are potent inhibitors of TRAIL- and CD95L-induced apoptosis, NF-κB activation, and the late JNK and p38 MAPK activation. cFLIP-mediated inhibition of CD95 and TRAIL DR could be of crucial importance during keratinocyte skin carcinogenesis and for the activation of innate and/or adaptive immune responses triggered by DR activation in the skin.
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c-FLIPS inhibits and c-FLIPL activates CASP8 by modulating CASP8 oligomerization.
“Compelling evidence indicates that the short variant of c-FLIP (c-FLIPS) and its long counterpart (c-FLIPL) inhibit and activate CASP8, respectively, by modulating CASP8 oligomerization [298–301].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [298]
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- Authors
- Kavuri, S. M., Geserick, P., Berg, D., Dimitrova, D. P., Feoktistova, M., Siegmund, D., Gollnick, H., Neumann, M., Wajant, H., & Leverkus, M.
- Affiliations
- Heidelberg University (DE)
- University of Würzburg (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- University of Tübingen (DE)
- Corresponding author
- Leverkus, Martin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 286
- Issue
- 19
- Pages
- 16631-16646
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3089506
- OpenAlex
- W1981075157
- Cited by
- 92
- References
- 66
- Citations by year
- 2026: 4 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 10 · 2016: 3 · 2015: 11 · 2014: 8 · 2013: 5 · 2012: 15
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- death receptors, Fas, TRAIL, caspase-8, death-inducing signaling complex, apoptosis, non-apoptotic signaling, NF-κB activation, JNK, p38 MAPK, interleukin-8, keratinocytes, skin carcinogenesis, innate immune response
- MeSH terms
- Cell Membrane, Cell Separation, Humans, Tumor Necrosis Factor-alpha, Signal Transduction, Keratinocytes, Apoptosis, fas Receptor, Protein Isoforms, Cell Line, Tumor, Caspase 8, Receptors, Death Domain, TNF-Related Apoptosis-Inducing Ligand, CASP8 and FADD-Like Apoptosis Regulating Protein
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