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p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

Author

Listed:
  • Yuri Shibata

    (Institute of Medical Science, University of Tokyo, Shirokane-dai)

  • Masaaki Oyama

    (Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokane-dai)

  • Hiroko Kozuka-Hata

    (Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokane-dai)

  • Xiao Han

    (Institute of Medical Science, University of Tokyo, Shirokane-dai)

  • Yuetsu Tanaka

    (Faculty of Medicine, University of the Ryukyus)

  • Jin Gohda

    (Institute of Medical Science, University of Tokyo, Shirokane-dai)

  • Jun-ichiro Inoue

    (Institute of Medical Science, University of Tokyo, Shirokane-dai
    Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Shirokane-dai)

Abstract

The persistent or excess activation of NF-κB causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the NEMO subunit of the IκB kinase (IKK) complex upon TNF-α or IL-1 stimulation, and inhibits IKK activation. p47 binds to Lys63-linked and linear polyubiquitin chains, which are conjugated to NEMO upon such stimulation. The binding of p47 to polyubiquitinated NEMO triggers the lysosomal degradation of NEMO, thereby inhibiting IKK activation. The silencing of p47 results in enhanced TNF-α- or IL-1-induced IKK activation, and an increased expression of genes encoding inflammatory mediators. Taken together, our results suggest that p47 is critical for negatively regulating stimulation-induced IKK activation in a manner that is mechanistically distinct from the previously characterized negative regulators, such as A20 and CYLD.

Suggested Citation

  • Yuri Shibata & Masaaki Oyama & Hiroko Kozuka-Hata & Xiao Han & Yuetsu Tanaka & Jin Gohda & Jun-ichiro Inoue, 2012. "p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO," Nature Communications, Nature, vol. 3(1), pages 1-13, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2068
    DOI: 10.1038/ncomms2068
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    Cited by:

    1. Ian Cooney & Heidi L. Schubert & Karina Cedeno & Olivia N. Fisher & Richard Carson & John C. Price & Christopher P. Hill & Peter S. Shen, 2024. "Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Xuetao Shi & Xin Xie & Yuanwen Guo & Junqi Zhang & Ziwen Gong & Kai Zhang & Jie Mei & Xinyao Xia & Haoxue Xia & Na Ning & Yutao Xiao & Qing Yang & Guo-Liang Wang & Wende Liu, 2024. "A fungal core effector exploits the OsPUX8B.2–OsCDC48-6 module to suppress plant immunity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Yang Xu & Han Han & Ian Cooney & Yuxuan Guo & Noah G. Moran & Nathan R. Zuniga & John C. Price & Christopher P. Hill & Peter S. Shen, 2022. "Active conformation of the p97-p47 unfoldase complex," Nature Communications, Nature, vol. 13(1), pages 1-8, December.

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