title: The c-FLIPL cleavage product p43FLIP promotes activation of extracellular signal-regulated kinase (ERK), nuclear factor κB (NF-κB), and caspase-8 and T cell survival.
abstract: Caspase-8 is now appreciated to govern both apoptosis following death receptor ligation and cell survival and growth via inhibition of the Ripoptosome. Cells must therefore carefully regulate the high level of caspase-8 activity during apoptosis versus the modest levels observed during cell growth. The caspase-8 paralogue c-FLIP is a good candidate for a molecular rheostat of caspase-8 activity. c-FLIP can inhibit death receptor-mediated apoptosis by competing with caspase-8 for recruitment to FADD. However, full-length c-FLIPL can also heterodimerize with caspase-8 independent of death receptor ligation and activate caspase-8 via an activation loop in the C terminus of c-FLIPL. This triggers cleavage of c-FLIPL at Asp-376 by caspase-8 to produce p43FLIP. The continued function of p43FLIP has, however, not been determined. We demonstrate that acute deletion of endogenous c-FLIP in murine effector T cells results in loss of caspase-8 activity and cell death. The lethality and caspase-8 activity can both be rescued by the transgenic expression of p43FLIP. Furthermore, p43FLIP associates with Raf1, TRAF2, and RIPK1, which augments ERK and NF-κB activation, IL-2 production, and T cell proliferation. Thus, not only is c-FLIP the initiator of caspase-8 activity during T cell activation, it is also an initial caspase-8 substrate, with cleaved p43FLIP serving to both stabilize caspase-8 activity and promote activation of pathways involved with T cell growth.
authors.affiliation: From the Vermont Center for Immunology and Infectious Diseases and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koenig
authors.forename: Iwona A
authors.initials: IA
authors.lastname: Buskiewicz
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fortner
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Russell
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asaoka
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D007376:Interleukin-2; D016328:NF-kappa B; D010446:Peptide Fragments; D047992:TNF Receptor-Associated Factor 2; D019908:Proto-Oncogene Proteins c-raf; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D053181:Caspase 8
keywords: Apoptosis; Caspase; Cell Proliferation; FLIP; Molecular Cell Biology; T Cell