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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon Type I / metabolism
  • Malaria, Cerebral / drug therapy
  • Malaria, Cerebral / immunology*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Neurogenic Inflammation / drug therapy
  • Neurogenic Inflammation / immunology*
  • Peptide Fragments / immunology
  • Plasmodium berghei / immunology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism*

Substances

  • DNA-Binding Proteins
  • Interferon Type I
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Transcription Factors
  • Trim25 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Ubiquitin-Specific Proteases
  • Usp15 protein, mouse