Article abstract
Nature Immunology 9, 1364 - 1370 (2008)
Published online: 9 November 2008 | doi:10.1038/ni.1678
Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-
B signaling
Sivakumar Vallabhapurapu1,4, Atsushi Matsuzawa1,4, WeiZhou Zhang1, Ping-Hui Tseng1, Jonathan J Keats2, Haopeng Wang3, Dario A A Vignali3, P Leif Bergsagel2 & Michael Karin1
Abstract
The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-
B (NF-B) signaling in resting cells by targeting NF-B–inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-B2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-B signaling have remained elusive. We now show that CD40 or BAFF receptor activation result in TRAF3 degradation in a cIAP1-cIAP2- and TRAF2-dependent way owing to enhanced cIAP1, cIAP2 TRAF3-directed ubiquitin ligase activity. Receptor-induced activation of cIAP1 and cIAP2 correlated with their K63-linked ubiquitination by TRAF2. Degradation of TRAF3 prevented association of NIK with the cIAP1-cIAP2-TRAF2 ubiquitin ligase complex, which resulted in NIK stabilization and NF-B2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Cancer Center, University of California, San Diego, California 93093, USA.
- Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105–2794, USA.
- These authors contributed equally to this work.
Correspondence to: Michael Karin1 e-mail: karinoffice@ucsd.edu
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