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

Nat Immunol. 2008 Dec;9(12):1364-70. doi: 10.1038/ni.1678. Epub 2008 Nov 9.

Abstract

The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-kappaB (NF-kappaB) signaling in resting cells by targeting NF-kappaB-inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-kappaB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-kappaB 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-kappaB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Inhibitor of Apoptosis Proteins / immunology
  • Inhibitor of Apoptosis Proteins / metabolism
  • Inverted Repeat Sequences
  • Mice
  • Mice, Mutant Strains
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / immunology*
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / immunology*
  • TNF Receptor-Associated Factor 3 / metabolism
  • Ubiquitination / immunology*

Substances

  • Inhibitor of Apoptosis Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase