OTUB1 modulates c-IAP1 stability to regulate signalling pathways
- Goncharov, T., Niessen, K., de Almagro, M.C., Izrael-Tomasevic, A., Fedorova, A.V., Varfolomeev, E., Arnott, D., Deshayes, K., Kirkpatrick, D.S., and Vucic, D.
- The EMBO journal 32(8): 1103-14 (Journal)
- Registered Authors
- c-IAP1, DUB, OTUB1, ubiquitin, TWEAK
- MeSH Terms
- Blood Vessels/embryology
- Cell Line
- Cysteine Endopeptidases/metabolism*
- Inhibitor of Apoptosis Proteins/metabolism*
- Mitogen-Activated Protein Kinase Kinases/metabolism
- NF-kappa B/metabolism
- Signal Transduction*
- 23524849 Full text @ EMBO J.
Goncharov, T., Niessen, K., de Almagro, M.C., Izrael-Tomasevic, A., Fedorova, A.V., Varfolomeev, E., Arnott, D., Deshayes, K., Kirkpatrick, D.S., and Vucic, D. (2013) OTUB1 modulates c-IAP1 stability to regulate signalling pathways. The EMBO journal. 32(8):1103-14.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes