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Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK

Abstract

Recent studies suggest that nuclear factor κB-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-κB 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.

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Figure 1: Nonredundancy of TRAF2 and TRAF3 and redundancy of cIAP1 and cIAP2 in suppression of the noncanonical NF-κB pathway.
Figure 2: Assembly of the NIK regulatory complex by TRAF2 and TRAF3.
Figure 3: Differential affinities of TRAF2 and TRAF3 for cIAPs and NIK.
Figure 4: Generation of a TRAF2-TRAF3 chimera.
Figure 5: The TRAF2-TRAF3 chimera, 3TD.
Figure 6: Receptor-induced stabilization of NIK after TRAF2 and TRAF3 degradation.
Figure 7: SMAC mimetic compounds mimic co-stimulatory properties of BAFF in B lymphocyte activation.
Figure 8: Rescue of the TRAF3-null phenotype by deletion of a single allele of NIK.

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Acknowledgements

We thank X. Wang (University of Texas Southwestern Medical Center) for the SMAC mimetic compound, L. Zawel and Novartis Pharmaceuticals for LBW242, and Amgen for BAFF and for Map3k14−/− mice. Supported by the US National Institutes of Health (R01GM078607 and R01GM57559, G.C.) and the Canadian Institutes of Health Research and Howard Hughes Medical Institute (R.G.K.).

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B.J.Z. and Y.W. designed and performed all the experiments unless otherwise stated. D.J.M. and H.H.C. did the siRNA knock-down assay in Birc2−/− and Birc3−/− cells. P.W.D. examined lymphocyte lineages and gene expression in mice. J.H. generated reconstituted MEFs and BCR-Abl–transformed Traf3−/− B cells. T.S. generated chimeric constructs. X.Y. provided the cIAP constructs. W.-c.Y. provided Traf2−/− 3T3 cells. T.W.M. provided Birc2−/− MEF cells. R.G.K. provided the cIAP antibody and Birc3−/− cells and supervised the work of D.J.M. and H.H.C. G.C. supervised the work, and all authors contributed to discussions and to the preparation of the manuscript.

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Correspondence to Genhong Cheng.

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Zarnegar, B., Wang, Y., Mahoney, D. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol 9, 1371–1378 (2008). https://doi.org/10.1038/ni.1676

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