2. Academic Validation
  3. CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

  • Cell Rep. 2016 Mar 29;14(12):2846-58. doi: 10.1016/j.celrep.2016.02.062.
Matous Hrdinka 1,  Berthe Katrine Fiil 1,  Mattia Zucca 1,  Derek Leske 1,  Katrin Bagola 1,  Monica Yabal 2,  Paul R Elliott 3,  Rune Busk Damgaard 1,  David Komander 3,  Philipp J Jost 2,  Mads Gyrd-Hansen 4
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
  • 2 III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany.
  • 3 Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
  • 4 Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: [email protected].
PMID: 26997266 DOI: 10.1016/j.celrep.2016.02.062
Abstract

Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub) is assembled by the linear ubiquitin assembly complex (LUBAC), and this is counteracted by the Met1-Ub-specific Deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the Deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components. Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production. Accordingly, Met1-Ub and Lys63-Ub were individually required for productive NOD2 signaling. Our study thus suggests that LUBAC, through its associated deubiquitinases, coordinates the deposition of not only Met1-Ub but also Lys63-Ub to ensure an appropriate response to innate immune receptor activation.

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