title: The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.
abstract: Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors: Rune Busk
authors: RB
authors: Damgaard
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors: Jennifer A
authors: JA
authors: Walker
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors: Paola
authors: P
authors: Marco-Casanova
authors: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors: Neil V
authors: NV
authors: Morgan
authors: Department of Clinical Genetics, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors: Hannah L
authors: HL
authors: Titheradge
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors: Paul R
authors: PR
authors: Elliott
authors: New Medicines, UCB Pharma, Slough SL1 3WE, UK.
authors: Duncan
authors: D
authors: McHale
authors: Department of Medical Genetics, University of Cambridge and Cambridge NIHR Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Electronic address: erm1000@medschl.cam.ac.uk.
authors: Eamonn R
authors: ER
authors: Maher
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. Electronic address: anm@mrc-lmb.cam.ac.uk.
authors: Andrew N J
authors: ANJ
authors: McKenzie
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. Electronic address: dk@mrc-lmb.cam.ac.uk.
authors: David
authors: D
authors: Komander
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D018095:Germ-Line Mutation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D000069285:Infliximab / Q000627:therapeutic use; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000276:immunology; D025821:Polyubiquitin / Q000378:metabolism; D017384:Sequence Deletion; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D025821:Polyubiquitin; D008715:Methionine; D000069285:Infliximab; D010450:Endopeptidases; C582107:OTULIN protein, human; D000072017:Deubiquitinating Enzymes