Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment

Malhotra, Sunny et al.[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. [Methods] 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. [Results] 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. [Conclusions] Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ. © 2013 EFNS.SM is an early stage researcher funded by the European Community's Seventh Framework Programme [FP7/2007–2013 under grant agreement no. 212877 (UEPHA*MS)]. RM and MM are supported by a Juan de la Cierva programme. The authors thank the Red Española de Esclerosis Múltiple (REEM) sponsored by the Fondo de Investigación Sanitaria (FIS), Ministry of Science and Innovation, Spain, and the Ajuts per donar Suport als Grups de Recerca de Catalunya, sponsored by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain.Peer Reviewe