Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.
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.
Vallabhapurapu
Sivakumar
S
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Cancer Center, University of California, San Diego, California 93093, USA.
Matsuzawa
Atsushi
A
Zhang
Weizhou
W
Tseng
Ping-Hui
PH
Keats
Jonathan J
JJ
Wang
Haopeng
H
Vignali
Dario A A
DA
Bergsagel
P Leif
PL
Karin
Michael
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology / Q000378:metabolism; D055029:Inverted Repeat Sequences; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology*; D000097782:NF-kappaB-Inducing Kinase
D051034:Inhibitor of Apoptosis Proteins; D017346:Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase