IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity.
The CD95 (Apo1/Fas)/CD95 ligand system plays pivotal roles in various aspects of immune regulation and function by triggering apoptosis. Besides the apoptosis signaling pathway, CD95 ligation also induces the activation of NF-kappaB. Previous studies suggest that IkappaB kinase (IKK) may be a key player in cell survival by mediating NF-kappaB activation. However, the roles of IKK in CD95 ligation-mediated apoptosis and NF-kappaB activation are still not clear. In this report, we show that expression of the caspase-resistant uncleavable IKKbeta (UCIKKbeta) mutant suppressed CD95 ligation-mediated cell death in HeLa cells. Furthermore, CD95 ligation induced much more cell death in IKKbeta-/- murine embryonic fibroblasts (MEFs) than in wild type MEFs, despite that IKK was only marginally activated upon CD95 ligation. Pretreatment of HeLa cells with a specific IKK inhibitor NEMO-binding domain (NBD) peptide blocked CD95 ligation-induced NF-kappaB transcriptional activity. And UCIKKbeta enhanced the basal NF-kappaB activity, and consequently led to higher NF-kappaB activity upon CD95 ligation in HeLa cells. Therefore, IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity.
Wang
Jing
J
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
Minemoto
Yuzuru
Y
Lin
Anning
A
Li
Yan
Y
Shen
Beifen
B
Zhang
Jiyan
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004622:Embryo, Mammalian / Q000166:cytology / Q000276:immunology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology*; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D051379:Mice; D017434:Protein Structure, Tertiary / Q000235:genetics; D013045:Species Specificity; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D053222:Fas Ligand Protein; D019014:fas Receptor; D051550:I-kappa B Kinase