Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment.
A role for cellular inhibitors of apoptosis (IAPs [cIAPs]) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist-induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA-mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIP(L) and not cFLIP(S) interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor-mediated cell death.
Geserick
Peter
P
Department of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Germany.
Hupe
Mike
M
Moulin
Maryline
M
Wong
W Wei-Lynn
WW
Feoktistova
Maria
M
Kellert
Beate
B
Gollnick
Harald
H
Silke
John
J
Leverkus
Martin
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism / Q000502:physiology; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
C119724:AGFG1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053222:Fas Ligand Protein; D020690:GTPase-Activating Proteins; D051034:Inhibitor of Apoptosis Proteins; D028861:Nuclear Pore Complex Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C490620:Ralbp1 protein, mouse; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor