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Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Author

Listed:
  • Ingrid E. Wertz

    (Discovery Oncology, Genentech
    Early Discovery Biochemistry, Genentech)

  • Kim Newton

    (Physiological Chemistry, Genentech)

  • Dhaya Seshasayee

    (Immunology, Genentech)

  • Saritha Kusam

    (Early Discovery Biochemistry, Genentech
    †Present address: Gilead Sciences, Inc., Department of Biology, Foster City, California 94404, USA.)

  • Cynthia Lam

    (Early Discovery Biochemistry, Genentech)

  • Juan Zhang

    (Immunology, Genentech)

  • Nataliya Popovych

    (Early Discovery Biochemistry, Genentech)

  • Elizabeth Helgason

    (Early Discovery Biochemistry, Genentech)

  • Allyn Schoeffler

    (Early Discovery Biochemistry, Genentech)

  • Surinder Jeet

    (Immunology, Genentech)

  • Nandhini Ramamoorthi

    (Immunology, Genentech)

  • Lorna Kategaya

    (Discovery Oncology, Genentech
    Early Discovery Biochemistry, Genentech)

  • Robert J. Newman

    (Molecular Biology, Genentech, South San Francisco)

  • Keisuke Horikawa

    (The John Curtin School of Medical Research, The Australian National University)

  • Debra Dugger

    (Physiological Chemistry, Genentech)

  • Wendy Sandoval

    (Protein Chemistry, Genentech)

  • Susmith Mukund

    (Structural Biology, Genentech)

  • Anuradha Zindal

    (Early Discovery Biochemistry, Genentech)

  • Flavius Martin

    (Immunology, Genentech)

  • Clifford Quan

    (Early Discovery Biochemistry, Genentech)

  • Jeffrey Tom

    (Early Discovery Biochemistry, Genentech)

  • Wayne J. Fairbrother

    (Early Discovery Biochemistry, Genentech)

  • Michael Townsend

    (Immunology, Genentech)

  • Søren Warming

    (Molecular Biology, Genentech, South San Francisco)

  • Jason DeVoss

    (Immunology, Genentech)

  • Jinfeng Liu

    (Bioinformatics, Genentech)

  • Erin Dueber

    (Early Discovery Biochemistry, Genentech)

  • Patrick Caplazi

    (Pathology, Genentech)

  • Wyne P. Lee

    (Immunology, Genentech)

  • Christopher C. Goodnow

    (Immunogenomics Laboratory, Garvan Institute of Medical Research)

  • Mercedesz Balazs

    (Immunology, Genentech)

  • Kebing Yu

    (Protein Chemistry, Genentech)

  • Ganesh Kolumam

    (Molecular Biology, Genentech, South San Francisco)

  • Vishva M. Dixit

    (Physiological Chemistry, Genentech)

Abstract

Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn’s disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.

Suggested Citation

  • Ingrid E. Wertz & Kim Newton & Dhaya Seshasayee & Saritha Kusam & Cynthia Lam & Juan Zhang & Nataliya Popovych & Elizabeth Helgason & Allyn Schoeffler & Surinder Jeet & Nandhini Ramamoorthi & Lorna Ka, 2015. "Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation," Nature, Nature, vol. 528(7582), pages 370-375, December.
  • Handle: RePEc:nat:nature:v:528:y:2015:i:7582:d:10.1038_nature16165
    DOI: 10.1038/nature16165
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    Cited by:

    1. Karin Vogel & Tobias Bläske & Marie-Kristin Nagel & Christoph Globisch & Shane Maguire & Lorenz Mattes & Christian Gude & Michael Kovermann & Karin Hauser & Christine Peter & Erika Isono, 2022. "Lipid-mediated activation of plasma membrane-localized deubiquitylating enzymes modulate endosomal trafficking," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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