title: OTUB1 modulates c-IAP1 stability to regulate signalling pathways.
abstract: The cellular inhibitor of apoptosis (c-IAP) proteins are E3 ubiquitin ligases that are critical regulators of tumour necrosis factor (TNF) receptor (TNFR)-mediated signalling. Through their E3 ligase activity c-IAP proteins promote ubiquitination of receptor-interaction protein 1 (RIP1), NF-κB-inducing kinase (NIK) and themselves, and regulate the assembly of TNFR signalling complexes. Consequently, in the absence of c-IAP proteins, TNFR-mediated activation of NF-κB and MAPK pathways and the induction of gene expression are severely reduced. Here, we describe the identification of OTUB1 as a c-IAP-associated deubiquitinating enzyme that regulates c-IAP1 stability. OTUB1 disassembles K48-linked polyubiquitin chains from c-IAP1 in vitro and in vivo within the TWEAK receptor-signalling complex. Downregulation of OTUB1 promotes TWEAK- and IAP antagonist-stimulated caspase activation and cell death, and enhances c-IAP1 degradation. Furthermore, knockdown of OTUB1 reduces TWEAK-induced activation of canonical NF-κB and MAPK signalling pathways and modulates TWEAK-induced gene expression. Finally, suppression of OTUB1 expression in zebrafish destabilizes c-IAP (Birc2) protein levels and disrupts fish vasculature. These results suggest that OTUB1 regulates NF-κB and MAPK signalling pathways and TNF-dependent cell death by modulating c-IAP1 stability.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goncharov
authors.forename: Kyle
authors.initials: K
authors.lastname: Niessen
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: de Almagro
authors.forename: Anita
authors.initials: A
authors.lastname: Izrael-Tomasevic
authors.forename: Anna V
authors.initials: AV
authors.lastname: Fedorova
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D006801:Humans; D006868:Hydrolysis; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D025801:Ubiquitin; D020929:Mitogen-Activated Protein Kinase Kinases; D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases