title: CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Matous
authors.initials: M
authors.lastname: Hrdinka
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Berthe Katrine
authors.initials: BK
authors.lastname: Fiil
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Zucca
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Leske
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bagola
authors.affiliation: III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany.
authors.forename: Monica
authors.initials: M
authors.lastname: Yabal
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Elliott
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Rune Busk
authors.initials: RB
authors.lastname: Damgaard
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Komander
authors.affiliation: III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich 81675, Germany.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: mads.gyrd-hansen@ludwig.ox.ac.uk.
authors.forename: Mads
authors.initials: M
authors.lastname: Gyrd-Hansen
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008715:Methionine / Q000737:chemistry / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D034741:RNA, Small Interfering; D025801:Ubiquitin; D008715:Methionine; D044767:Ubiquitin-Protein Ligases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D010450:Endopeptidases; D000072017:Deubiquitinating Enzymes; D008239:Lysine