• An Erratum to this article was published on 16 November 2016

This article has been updated


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.

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Change history

  • 24 October 2016

    In the version of this article initially published online, the symbol for the gene encoding granzyme B was incorrect (Gmzb) in the text in the third paragraph of the fourth subsection of Results and Figure 5d, and the symbol for the gene encoding granzyme A was incorrect (Gmza) in Figure 6h. These should be Gzmb and Gzma, respectively. The errors have been corrected for the print, PDF and HTML versions of this article.


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We thank R. Van Bruggen, S. Gauthier, P. D'Arcy and G. Perreault for assistance in the ENU project, and C. Meunier for technical assistance. Supported by the Canadian Institutes of Health Research (MOP119342 and MOP133487 to P.G. and S.V.) and Amorchem (PT63088).

Author information


  1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

    • Sabrina Torre
    • , Gabriel A Leiva-Torres
    • , Jacek Majewski
    • , Mark Lathrop
    • , Silvia M Vidal
    •  & Philippe Gros
  2. McGill Center for Complex Traits, McGill University, Montreal, Quebec, Canada.

    • Sabrina Torre
    • , Maria J Polyak
    • , David Langlais
    • , Nassima Fodil
    • , James M Kennedy
    • , Irena Radovanovic
    • , Joanne Berghout
    • , Gabriel A Leiva-Torres
    • , Silvia M Vidal
    •  & Philippe Gros
  3. Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

    • Maria J Polyak
    • , David Langlais
    • , Nassima Fodil
    • , James M Kennedy
    • , Irena Radovanovic
    • , Joanne Berghout
    •  & Philippe Gros
  4. Department of Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada.

    • Connie M Krawczyk
  5. Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada.

    • Subburaj Ilangumaran
  6. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.

    • Karen Mossman
  7. Department of Medicine, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.

    • Chen Liang
  8. Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany.

    • Klaus-Peter Knobeloch
  9. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

    • Luke M Healy
    •  & Jack Antel
  10. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.

    • Nathalie Arbour
    •  & Alexandre Prat
  11. McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada.

    • Jacek Majewski
    •  & Mark Lathrop


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S.T., M.L., J.M. and J.B. contributed to mutation identification. S.T. performed all of the PbA experiments. M.J.P. performed all of the EAE experiments. S.T. and M.J.P. performed biochemical work. I.R., J.M.K. and S.T. performed the immunophenotyping experiments. D.L. performed RNA sequencing analyses, and S.T. carried out validations by RT-qPCR. Primary cells from brain were provided and characterized by J.A., N.A., A.P., M.J.P. and L.M.H., with additional contribution from G.A.L.-T., S.I., K.M., C.L. and K.P.K. kindly provided gene knockout animals. S.T. performed Listeria experiments with guidance from C.M.K. N.F. performed BM transplant experiments. J.B., J.M. and M.L. performed analyses of exome sequences. P.G. and S.M.V. supervised the project, helped to design experiments and analyzed data. P.G., S.T., D.L., M.J.P. and N.F. wrote the first draft of the manuscript. All of the authors provided helpful comments on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philippe Gros.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8

Excel files

  1. 1.

    Supplementary Table 1

    List of dys-regulated genes in Usp15L749R mutant mice undergoing ECM and EAE models of neuroinflammatory diseases, related to Fig. 4b.

  2. 2.

    Supplementary Table 2

    Detailed matrix of leading edge analysis clustering performed on ECM and EAE depleted gene signatures in Usp15L749R mutant mice, related to Fig. 5a.

  3. 3.

    Supplementary Table 3

    qPCR validation primers, related to Fig. 5c-f.

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