De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

• Published in: Cell death and differentiation Vol. 19; no. 5; pp. 891 - 899
• Main Authors: Mahul-Mellier, A-L, Pazarentzos, E, Datler, C, Iwasawa, R, AbuAli, G, Lin, B, Grimm, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2012; Nature Publishing Group
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Caspase 8 - genetics; Caspase 8 - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line; Cell Line, Tumor; Endopeptidases - genetics; Endopeptidases - metabolism; Flow Cytometry; HeLa Cells; Humans; Immunoprecipitation; Life Sciences; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Original Paper; Phosphorylation - drug effects; Phosphorylation - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Stem Cells; TNF Receptor-Associated Factor 2 - genetics; TNF Receptor-Associated Factor 2 - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitin Thiolesterase; NF; apoptosis; B; TNF; ubiquitin
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/cdd.2011.185

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 I κ B α , which is essential to inactivate the anti-apoptotic transcription factor NF- κ B. 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- κ B activation and protects cells against TNF-induced cell death.