1. USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.
- Author
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Torre S, Polyak MJ, Langlais D, Fodil N, Kennedy JM, Radovanovic I, Berghout J, Leiva-Torres GA, Krawczyk CM, Ilangumaran S, Mossman K, Liang C, Knobeloch KP, Healy LM, Antel J, Arbour N, Prat A, Majewski J, Lathrop M, Vidal SM, and Gros P
- Subjects
- Animals, DNA-Binding Proteins genetics, Encephalomyelitis, Autoimmune, Experimental drug therapy, HEK293 Cells, Humans, Immunity, Innate, Interferon Type I metabolism, Malaria, Cerebral drug therapy, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Molecular Targeted Therapy, Myelin-Oligodendrocyte Glycoprotein immunology, Neurogenic Inflammation drug therapy, Peptide Fragments immunology, Plasmodium berghei immunology, Transcription Factors genetics, Ubiquitin-Specific Proteases genetics, DNA-Binding Proteins metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Malaria, Cerebral immunology, Neurogenic Inflammation immunology, Transcription Factors metabolism, Ubiquitin-Specific Proteases metabolism
- 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 (Usp15
L749R ) 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.- Published
- 2017
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