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

• Published in: Cell reports (Cambridge) Vol. 20; no. 4; pp. 846 - 853
• Main Authors: Romania, Paolo, Cifaldi, Loredana, Pignoloni, Benedetta, Starc, Nadia, D’Alicandro, Valerio, Melaiu, Ombretta, Li Pira, Giuseppina, Giorda, Ezio, Carrozzo, Rosalba, Bergvall, Monika, Bergström, Tomas, Alfredsson, Lars, Olsson, Tomas, Kockum, Ingrid, Seppälä, Ilkka, Lehtimäki, Terho, Hurme, Mikko A., Hengel, Hartmut, Santoni, Angela, Cerboni, Cristina, Locatelli, Franco, D’Amato, Mauro, Fruci, Doriana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-07-2017; Elsevier
• Subjects: 3' Untranslated Regions - genetics; Aminopeptidases - genetics; Aminopeptidases - metabolism; antigen processing and presentation; CD8-Positive T-Lymphocytes - metabolism; Cell Biology; Cellbiologi; CELLS; Cytomegalovirus - genetics; Cytomegalovirus Infections - enzymology; Cytomegalovirus Infections - genetics; cytotoxic T cells; ENDOPLASMIC-RETICULUM; ERAP1; EXPRESSION; genetic variant; Genetic Variation - genetics; Genotype; human cytomegalovirus; Humans; IMMUNITY; INFECTION; Medicin och hälsovetenskap; MHC class I molecules; microRNA; MICRORNAS; MicroRNAs - genetics; MicroRNAs - metabolism; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - metabolism; MOLECULES; Multiple Sclerosis - enzymology; Multiple Sclerosis - genetics; MULTIPLE-SCLEROSIS; Protein Binding; RISK; RNA, Messenger - genetics; RNA, Viral - genetics; serology; T-Lymphocytes, Cytotoxic - metabolism; viral immunoevasion; multiple sclerosis; ERAP1; serology; microRNA; antigen processing and presentation; genetic variant; human cytomegalovirus; viral immunoevasion; cytotoxic T cells; MHC class I molecules
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.06.084

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.
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•HCMV miR-112-5p targets ERAP1, preventing the presentation of viral epitopes to CTLs•The rs17481334 variant G preserves ERAP1 from miR-UL112-5p-mediated degradation•HCMV-infected GG cells are more efficiently lysed by HCMV-peptide-specific CTLs•Decreased HCMV seropositivity is detected among multiple sclerosis GG patients
Romania et al. identify a single-nucleotide polymorphism in ERAP1 gene, which represents a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy, with potential implications for individual susceptibility to viral infection and other diseases.