Format

Send to

Choose Destination
Nat Immunol. 2017 Jan;18(1):54-63. doi: 10.1038/ni.3581. Epub 2016 Oct 10.

USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.
3
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
4
Department of Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada.
5
Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada.
6
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
7
Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
8
Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany.
9
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
10
Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
11
McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada.

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.

PMID:
27721430
DOI:
10.1038/ni.3581
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center