Article abstract
Nature Immunology 9, 1371 - 1378 (2008)
Published online: 9 November 2008 | doi:10.1038/ni.1676
Noncanonical NF-
B activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK
Brian J Zarnegar1,5, Yaya Wang1,5, Douglas J Mahoney2, Paul W Dempsey1, Herman H Cheung2, Jeannie He1, Travis Shiba1, Xiaolu Yang3, Wen-chen Yeh4, Tak W Mak4, Robert G Korneluk2 & Genhong Cheng1
Abstract
Recent studies suggest that nuclear factor 
B-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-B 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.
- Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, 609 Charles E. Young Drive East, Los Angeles, California 90095, USA.
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
- Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
- The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada.
- These authors contributed equally to this work.
Correspondence to: Genhong Cheng1 e-mail: gcheng@mednet.ucla.edu
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