Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation

Ingrid E. Wertz (), Kim Newton, Dhaya Seshasayee, Saritha Kusam, Cynthia Lam, Juan Zhang, Nataliya Popovych, Elizabeth Helgason, Allyn Schoeffler, Surinder Jeet, Nandhini Ramamoorthi, Lorna Kategaya, Robert J. Newman, Keisuke Horikawa, Debra Dugger, Wendy Sandoval, Susmith Mukund, Anuradha Zindal, Flavius Martin, Clifford Quan, Jeffrey Tom, Wayne J. Fairbrother, Michael Townsend, Søren Warming, Jason DeVoss, Jinfeng Liu, Erin Dueber, Patrick Caplazi, Wyne P. Lee, Christopher C. Goodnow, Mercedesz Balazs, Kebing Yu, Ganesh Kolumam and Vishva M. Dixit ()
Additional contact information
Ingrid E. Wertz: Discovery Oncology, Genentech
Kim Newton: Physiological Chemistry, Genentech
Dhaya Seshasayee: Immunology, Genentech
Saritha Kusam: Early Discovery Biochemistry, Genentech
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
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

Nature, 2015, vol. 528, issue 7582, 370-375

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature16165

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