title: De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF.
abstract: Components of the TNFR1 complex are subject to dynamic ubiquitination that impacts on their effects as signalling factors. We have found that the ubiquitin-specific protease USP2a has a pivotal role in the decision for cell death or survival by the TNFR1 complex. This enzyme is a novel component of the TNFR1 complex that is recruited upon ligand binding and controls the signalling activity of the TNFR1-interacting protein RIP1 by removing its K63-linked ubiquitin chains. USP2a similarly de-ubiquitinates TRAF2, a ubiquitin-ligase recruited to the TNFR1 complex. During the TNF response the activity of USP2a on RIP1 and TRAF2 is required for the efficient reappearance of IκBα, which is essential to inactivate the anti-apoptotic transcription factor NF-κB. The effects of USP2a culminate in the conversion of the anti-apoptotic TNFR1 complex I into the pro-apoptotic TNFR1 complex II. Consequently, downregulation of USP2a promotes NF-κB activation and protects cells against TNF-induced cell death.
authors.affiliation: Imperial College London, Experimental Medicine and Toxicology, Hammersmith Campus, Du Cane Road, Burlington Danes Building, London W12 0NN, UK.
authors.forename: A-L
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.forename: E
authors.initials: E
authors.lastname: Pazarentzos
authors.forename: C
authors.initials: C
authors.lastname: Datler
authors.forename: R
authors.initials: R
authors.lastname: Iwasawa
authors.forename: G
authors.initials: G
authors.lastname: AbuAli
authors.forename: B
authors.initials: B
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Grimm
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase
chemical_list: C119724:AGFG1 protein, human; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase; D053181:Caspase 8