Mind bomb 1 regulation of cFLIP interactions.
Mind bomb 1 (Mib1) is a multidomain E3 ligase that directs ubiquitination of the Notch ligands Delta and Jagged to promote their endocytosis. Here we examine Notch-independent functions of Mib1 and find that its activities are linked to the initiation of the extrinsic cell death pathway. Expression of Mib1 induces a spontaneous, caspase-dependent cell death. Consistent with this, depletion of endogenous Mib1 decreases tumor-necrosis factor (TNF)-induced cell death. Mib1 was found to bind to cellular Fas-associated death domain (FADD)-like IL-1b converting enzyme (FLICE)-like inhibitory proteins (cFLIP-L and cFLIP-S), whereas only cFLIP-s can inhibit Mib1-induced cell death. The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP, which activates caspase-8 and induces cell death. Collectively, these results suggest that in addition to a central role in Notch signaling, Mib1 has an important role in regulating the extrinsic cell death pathway.
Zhang
Liguo
L
Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA.
Gallagher
Patricia J
PJ
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D047468:Immunoprecipitation; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8