OTUB1 modulates c‐IAP1 stability to regulate signalling pathways. (22nd March 2013)
- Record Type:
- Journal Article
- Title:
- OTUB1 modulates c‐IAP1 stability to regulate signalling pathways. (22nd March 2013)
- Main Title:
- OTUB1 modulates c‐IAP1 stability to regulate signalling pathways
- Authors:
- Goncharov, Tatiana
Niessen, Kyle
de Almagro, Maria Cristina
Izrael‐Tomasevic, Anita
Fedorova, Anna V
Varfolomeev, Eugene
Arnott, David
Deshayes, Kurt
Kirkpatrick, Donald S
Vucic, Domagoj - Abstract:
- <abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p><abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p> </abstract> … (more)
- Is Part Of:
- EMBO journal. Volume 32:Number 8(2013)
- Journal:
- EMBO journal
- Issue:
- Volume 32:Number 8(2013)
- Issue Display:
- Volume 32, Issue 8 (2013)
- Year:
- 2013
- Volume:
- 32
- Issue:
- 8
- Issue Sort Value:
- 2013-0032-0008-0000
- Page Start:
- 1103
- Page End:
- 1114
- Publication Date:
- 2013-03-22
- Subjects:
- Molecular biology -- Periodicals
572.805 - Journal URLs:
- http://onlinelibrary.wiley.com/ ↗
- DOI:
- 10.1038/emboj.2013.62 ↗
- Languages:
- English
- ISSNs:
- 0261-4189
- Deposit Type:
- Legaldeposit
- View Content:
- Available online (eLD content is only available in our Reading Rooms) ↗
- Physical Locations:
- British Library DSC - 3733.085000
British Library DSC - BLDSS-3PM
British Library HMNTS - ELD Digital store - Ingest File:
- 3733.xml