Bcl10 activates the NF-κB pathway through ubiquitination of NEMO (original) (raw)

Nature volume 427, pages 167–171 (2004)Cite this article

Abstract

The NF-κB family of transcription factors is activated in response to many stimuli, including pro-inflammatory cytokines, environmental stresses and, in the case of B and T lymphocytes, by antigenic stimulation1,2. Bcl10 is essential for NF-κB activation by T- and B-cell receptors. T and B lymphocytes from Bcl10-deficient mice fail to activate NF-κB in response to antigen-receptor stimulation and, as a consequence, are unable to proliferate3. Bcl10 overexpression is sufficient to activate NF-κB, a process that requires the NF-κB essential modulator NEMO (also known as IKK-γ), which is the regulatory subunit of the IκB kinase complex4. However, the cellular mechanism by which Bcl10 activates the NF-κB pathway remains unclear. Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation. Paracaspase and a ubiquitin-conjugating enzyme (UBC13) were both required for Bcl10-induced NEMO ubiquitination and subsequent NF-κB activation. Furthermore, short interfering RNAs that reduced the expression of paracaspase and UBC13 abrogated the effects of Bcl10. Thus, the adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO.

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Acknowledgements

We thank members of the Dixit laboratory for discussions and support; K. Newton for critical reading of the manuscript; S. Sun for the JM4.5.2 cell line; S. Yamaoka for the 5R cell line; R. Baker for Usp2; M. Yan for experimental advice; Z. Zhang for bioinformatics analysis; P. Andersen for antibody preparation; P. Yin for protein purification; and the Genentech Sequencing Core. I.E.W. is funded by a PSTP fellowship from the University of California at Davis.

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Authors and Affiliations

  1. Department of Molecular Oncology, Genentech Inc. 1 DNA Way, South San Francisco, California, 94080, USA
    Honglin Zhou, Ingrid Wertz, Karen O'Rourke & Vishva M. Dixit
  2. Department of Protein Engineering, Genentech Inc. 1 DNA Way, South San Francisco, California, 94080, USA
    Mark Ultsch
  3. Department of Molecular Biology, Genentech Inc. 1 DNA Way, South San Francisco, California, 94080, USA
    Somasekar Seshagiri & Michael Eby
  4. Department of Biological Chemistry, School of Medicine, University of California at Davis, Davis, California, 95616, USA
    Ingrid Wertz
  5. Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5, Canada
    Wei Xiao

Authors

  1. Honglin Zhou
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  2. Ingrid Wertz
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  3. Karen O'Rourke
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  4. Mark Ultsch
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  5. Somasekar Seshagiri
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  6. Michael Eby
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  7. Wei Xiao
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  8. Vishva M. Dixit
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Correspondence toVishva M. Dixit.

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Zhou, H., Wertz, I., O'Rourke, K. et al. Bcl10 activates the NF-κB pathway through ubiquitination of NEMO.Nature 427, 167–171 (2004). https://doi.org/10.1038/nature02273

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