Article
- The EMBO Journal (2005) 24, 1886 - 1898
- doi:10.1038/sj.emboj.7600649
Published online: 28 April 2005
Subject Category:
TNF-
induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination
Chuan-Jin Wu1, Dietrich B Conze1, Xiaoming Li1,a, Sai-Xia Ying1, John A Hanover2 and Jonathan D Ashwell1
- Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, MD, USA
Correspondence to:
Jonathan D Ashwell, Laboratory of Immune Cell Biology, National Cancer Institute, NIDDKD, National Institutes of Health, Bethesda, MD 20892, USA. Tel.: +1 301 496 4931; Fax: +1 301 402 4844; E-mail: jda@pop.nci.nih.gov
aPresent address: Department of Otolaryngology Head & Neck Surgery, Bethune International Peace Hospital, Shijiazhuang 050082, PR China
Received 17 September 2004; Accepted 22 March 2005
Abstract
Signaling through tumor necrosis factor receptor 2 (TNF-R2) results in ubiquitination of TRAF2 by the E3 c-IAP1. In this report, we confirm that TRAF2 translocates to a Triton X-100 (TX)-insoluble compartment upon TNF-R2 engagement. Moreover, TRAF2 ubiquitination occurs in this compartment, from which TRAF2 is degraded in a proteasome-dependant manner. Confocal microscopy demonstrated that the TX-insoluble compartment is perinuclear and co-localizes with endoplasmic reticulum (ER) markers. The ER transmembrane Ubc6 bound to c-IAP1 and served as a cognate E2 for c-IAP1's E3 activity in vitro. Furthermore, Ubc6 co-localized with translocated TRAF2/c-IAP1 in the ER-associated compartment in vivo, and a catalytically inactive Ubc6 mutant inhibited TNF-
-induced, TNF-R2-dependent TRAF2 degradation. These results indicate that upon TNF-R2 signaling, translocation of TRAF2 and c-IAP1 to an ER-associated, Ubc6-containing perinuclear compartment is required for the ubiquitination of TRAF2 by c-IAP1. Therefore, the ER plays a key role in the TNF-R-mediated signal transduction cascade by acting as a site of assembly for E2/E3/substrate complexes.
Keywords:
- c-IAP1,
- intracellular translocation,
- TNFR,
- TRAF2,
- ubiquitination
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