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TNF‐α induced c‐IAP1/TRAF2 complex translocation to a Ubc6‐containing compartment and TRAF2 ubiquitination
Author(s) -
Wu ChuanJin,
Conze Dietrich B,
Li Xiaoming,
Ying SaiXia,
Hanover John A,
Ashwell Jonathan D
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600649
Subject(s) - traf2 , biology , chromosomal translocation , ubiquitin , microbiology and biotechnology , immunoprecipitation , tumor necrosis factor alpha , cancer research , tumor necrosis factor receptor , genetics , cell culture , gene , immunology
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‐α‐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.