Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK.
Recent studies suggest that nuclear factor kappaB-inducing kinase (NIK) is suppressed through constitutive proteasome-mediated degradation regulated by TRAF2, TRAF3 and cIAP1 or cIAP2. Here we demonstrated that the degradation of NIK occurs upon assembly of a regulatory complex through TRAF3 recruitment of NIK and TRAF2 recruitment of cIAP1 and cIAP2. In contrast to TRAF2 and TRAF3, cIAP1 and cIAP2 seem to play redundant roles in the degradation of NIK, as inhibition of both cIAPs was required for noncanonical NF-kappaB activation and increased survival and proliferation of primary B lymphocytes. Furthermore, the lethality of TRAF3 deficiency in mice could be rescued by a single NIK gene, highlighting the importance of tightly regulated NIK.
Zarnegar
Brian J
BJ
Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, 609 Charles E. Young Drive East, Los Angeles, California 90095, USA.
Wang
Yaya
Y
Mahoney
Douglas J
DJ
Dempsey
Paul W
PW
Cheung
Herman H
HH
He
Jeannie
J
Shiba
Travis
T
Yang
Xiaolu
X
Yeh
Wen-Chen
WC
Mak
Tak W
TW
Korneluk
Robert G
RG
Cheng
Genhong
G
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D015151:Immunoblotting; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3