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

Paolo Romania, Loredana Cifaldi, Benedetta Pignoloni, Nadia Starc, Valerio D'Alicandro, Ombretta Melaiu, Giuseppina Li Pira, Ezio Giorda, Rosalba Carrozzo, Monika Bergvall, Tomas Bergström, Lars Alfredsson, Tomas Olsson, Ingrid Kockum, Ilkka Seppälä, Terho Lehtimäki, Mikko A. Hurme, Hartmut Hengel, Angela Santoni, Cristina CerboniFranco Locatelli, Mauro D'Amato, Doriana Fruci

Research output: Contribution to journalArticlepeer-review

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 3′ UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3′ UTR of ERAP1 A variant, but not the 3′ 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 adult-onset 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.

Original languageEnglish
Pages (from-to)846-853
Number of pages8
JournalCell Reports
Volume20
Issue number4
DOIs
Publication statusPublished - Jul 25 2017

Keywords

  • antigen processing and presentation
  • cytotoxic T cells
  • ERAP1
  • genetic variant
  • human cytomegalovirus
  • MHC class I molecules
  • microRNA
  • multiple sclerosis
  • serology
  • viral immunoevasion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion'. Together they form a unique fingerprint.

Cite this