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 journalArticlepeer-review

419 Citations (Scopus)

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
Pages (from-to)1364-1370
Number of pages7
JournalNature Immunology
Volume9
Issue number12
DOIs
Publication statusPublished - 2008 Nov 7
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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