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.

Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion / Romania, Paolo; Cifaldi, Loredana; Pignoloni, Benedetta; Starc, Nadia; D'Alicandro, Valerio; Melaiu, Ombretta; Pira, Giuseppina Li; Giorda, Ezio; Carrozzo, Rosalba; Bergvall, Monika; Bergstrã¶m, Tomas; Alfredsson, Lars; Olsson, Tomas; Kockum, Ingrid; Seppã¤lã¤, Ilkka; Lehtimã¤ki, Terho; Hurme, Mikko A.; Hengel, Hartmut; Santoni, Angela; Cerboni, Cristina; Locatelli, Franco; D'Amato, Mauro; Fruci, Doriana. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 20:4(2017), pp. 846-853. [10.1016/j.celrep.2017.06.084]

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

Romania, Paolo
Primo
;
Pignoloni, Benedetta;D'alicandro, Valerio
Methodology
;
Santoni, Angela;Cerboni, Cristina;Locatelli, Franco;
2017

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.
2017
antigen processing and presentation; cytotoxic t cells; erap1; genetic variant; human cytomegalovirus; mhc class I molecules; microRNA; multiple sclerosis; serology; viral immunoevasion;
01 Pubblicazione su rivista::01a Articolo in rivista
Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion / Romania, Paolo; Cifaldi, Loredana; Pignoloni, Benedetta; Starc, Nadia; D'Alicandro, Valerio; Melaiu, Ombretta; Pira, Giuseppina Li; Giorda, Ezio; Carrozzo, Rosalba; Bergvall, Monika; Bergstrã¶m, Tomas; Alfredsson, Lars; Olsson, Tomas; Kockum, Ingrid; Seppã¤lã¤, Ilkka; Lehtimã¤ki, Terho; Hurme, Mikko A.; Hengel, Hartmut; Santoni, Angela; Cerboni, Cristina; Locatelli, Franco; D'Amato, Mauro; Fruci, Doriana. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 20:4(2017), pp. 846-853. [10.1016/j.celrep.2017.06.084]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1017807
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