Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling

Sivakumar Vallabhapurapu, Atsushi Matsuzawa, Wei Zhou Zhang, Ping Hui Tseng, Jonathan J. Keats, Haopeng Wang, Dario A.A. Vignali, P. Leif Bergsagel, Michael Karin

Research output: Contribution to journalArticle

414 Scopus citations

Abstract

The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-κB (NF-κB) signaling in resting cells by targeting NF-κB-inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-κB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-κB 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-κB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.

Original languageEnglish (US)
Pages (from-to)1364-1370
Number of pages7
JournalNature immunology
Volume9
Issue number12
DOIs
StatePublished - Nov 7 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Vallabhapurapu, S., Matsuzawa, A., Zhang, W. Z., Tseng, P. H., Keats, J. J., Wang, H., Vignali, D. A. A., Bergsagel, P. L., & Karin, M. (2008). Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nature immunology, 9(12), 1364-1370. https://doi.org/10.1038/ni.1678