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

Nature immunology (2008-11-11)
Sivakumar Vallabhapurapu, Atsushi Matsuzawa, Weizhou Zhang, Ping-Hui Tseng, Jonathan J Keats, Haopeng Wang, Dario A A Vignali, P Leif Bergsagel, Michael Karin
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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
3X FLAG® Peptide, lyophilized powder
Sigma-Aldrich
Sepharose® 6B, 6% Beaded Agarose, 45-165 μm (wet), fractionation range 10,000-1,000,000 Da (dextrans)
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Anti-IKKβ Antibody, clone 10AG2, clone 10AG2, Upstate®, from mouse