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

Nature Immunology volume 9, pages 13641370 (2008) | Download Citation

Abstract

The adaptor and signaling proteins TRAF2, TRAF3, cIAP1 and cIAP2 may inhibit alternative nuclear factor-κB (NF-κB) signaling in resting cells by targeting NF-κB–inducing kinase (NIK) for ubiquitin-dependent degradation, thus preventing processing of the NF-κB2 precursor protein p100 to release p52. However, the respective functions of TRAF2 and TRAF3 in NIK degradation and activation of alternative NF-κB 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-κB2-p100 processing. Constitutive activation of this pathway causes perinatal lethality and lymphoid defects.

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Acknowledgements

We thank T. Mak (University of Toronto), H. Kikutani (Osaka University) and Amgen Inc. for the Traf2+/−, Traf3+/− and Map3k14+/− mouse strains; P.M. Chumakov (Cleveland Clinic) for the pLSLPw lentiviral vector; Z. Ronai and J. Reed (Burnham Institute) for some of the expression vectors; and Santa Cruz Biotechnology for the donated antibodies. Supported by the US National Institutes of Health (M.K., D.A.A.V. and H.W.), the Kanzawa Medical Research Foundation (A.M., in part), the American Lung Association (P.-H.T., in part), a Cancer Center core grant and the American Lebanese Syrian Associated Charities (D.A.A.V. and H.W.) and the American Cancer Society (M.K.).

Author information

Author notes

    • Sivakumar Vallabhapurapu
    •  & Atsushi Matsuzawa

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Cancer Center, University of California, San Diego, California 93093, USA.

    • Sivakumar Vallabhapurapu
    • , Atsushi Matsuzawa
    • , WeiZhou Zhang
    • , Ping-Hui Tseng
    •  & Michael Karin
  2. Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.

    • Jonathan J Keats
    •  & P Leif Bergsagel
  3. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105–2794, USA.

    • Haopeng Wang
    •  & Dario A A Vignali

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Contributions

S.V. and M.K. planned and designed all experiments and wrote the manuscript. S.V. performed most experiments. A.M. performed the ubiquitination experiments. W.Z. performed immunoprecipitation experiments. H.W. and D.A.A.V. provided Lys63-specific anti-ubiquitin. J.J.K. and P.L.B. provided the cIAP-wild-type and cIAP-deficient multiple myeloma cells. P.-H.T. made CD40-expressing HEK-293T cells.

Corresponding author

Correspondence to Michael Karin.

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DOI

https://doi.org/10.1038/ni.1678

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