Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment
Article first published online: 22 MAY 2013
© 2013 The Author(s) European Journal of Neurology © 2013 EFNS
European Journal of Neurology
Volume 20, Issue 10, pages 1390–1397, October 2013
How to Cite
Malhotra, S., Morcillo-Suárez, C., Nurtdinov, R., Rio, J., Sarro, E., Moreno, M., Castilló, J., Navarro, A., Montalban, X. and Comabella, M. (2013), Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment. European Journal of Neurology, 20: 1390–1397. doi: 10.1111/ene.12193
- Issue published online: 12 SEP 2013
- Article first published online: 22 MAY 2013
- Manuscript Accepted: 16 APR 2013
- Manuscript Received: 17 JAN 2013
- European Community's Seventh Framework Programme . Grant Number: 212877
- Fondo de Investigación Sanitaria (FIS), Ministry of Science and Innovation, Spain
- Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)
- genetic susceptibility;
- multiple sclerosis;
- response to treatment;
- USP18 polymorphisms
Background and purpose
Ubiquitin specific peptidase 18 (USP18) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of USP18 in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls.
Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse-onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non-responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for USP18 and its target ISG15 were performed by real-time polymerase chain reaction.
Two USP18 haplotypes were significantly associated with MS, TG and CG. Additional experiments revealed that CG carriers were characterized by lower USP18 gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, AA homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, USP18 expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes.
Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ.