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Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion

Journal article
Authors P. Romania
L. Cifaldi
B. Pignoloni
N. Starc
V. D'Alicandro
O. Melaiu
G. L. Pira
E. Giorda
R. Carrozzo
M. Bergvall
Tomas Bergström
L. Alfredsson
T. Olsson
I. Kockum
I. Seppala
T. Lehtimaki
M. A. Hurme
H. Hengel
A. Santoni
C. Cerboni
F. Locatelli
M. D'Amato
D. Fruci
Published in Cell Reports
Volume 20
Issue 4
Pages 846-853
ISSN 2211-1247
Publication year 2017
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 846-853
Language en
Links dx.doi.org/10.1016/j.celrep.2017.06...
Keywords MULTIPLE-SCLEROSIS, ENDOPLASMIC-RETICULUM, INFECTION, EXPRESSION, MICRORNAS, MOLECULES, IMMUNITY, CELLS, RISK, Cell Biology
Subject categories Cell Biology

Abstract

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 30 UTR, preserves ERAP1 from miR-UL1125p-mediated degradation. Specifically, HCMV miRUL112-5p binds the 30 UTR of ERAP1 A variant, but not the 30 UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adultonset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.

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