title: USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.
abstract: Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15L749R) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15L749R-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ. In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Torre
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Maria J
authors.identifier: 0000-0003-3762-9278
authors.initials: MJ
authors.lastname: Polyak
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Nassima
authors.initials: N
authors.lastname: Fodil
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: James M
authors.initials: JM
authors.lastname: Kennedy
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Irena
authors.identifier: 0000-0002-3823-3729
authors.initials: I
authors.lastname: Radovanovic
authors.affiliation: McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Berghout
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Leiva-Torres
authors.affiliation: Department of Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Krawczyk
authors.affiliation: Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Mossman
authors.affiliation: Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Luke M
authors.initials: LM
authors.lastname: Healy
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
authors.affiliation: Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
authors.affiliation: Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.identifier: 0000-0003-3572-9558
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D020078:Neurogenic Inflammation / Q000188:drug therapy / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D010962:Plasmodium berghei / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D007370:Interferon Type I; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D014157:Transcription Factors; C490034:Trim25 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D064570:Ubiquitin-Specific Proteases; C579225:Usp15 protein, mouse