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; Bergström, Tomas; Alfredsson, Lars; Olsson, Tomas; Kockum, Ingrid; Seppälä, Ilkka; Lehtimäki, Terho; Hurme, Mikko; Hengel, Hartmut; Santoni, Angela; Cerboni, Cristina; Locatelli, Franco; D’Amato, Mauro; Fruci, Doriana

doi:10.1016/j.celrep.2017.06.084

Cited by 33 publications

(37 citation statements)

References 40 publications

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“…However, the HCMV gene expression pro le has not been explored in CRC tissue, which was evaluated by next-generation sequencing in this study. A total of 119 HCMV genes were detected in CRC tissues; 18 HCMV viral genes were detected in patients with SLE [33], among which 17 were detected except for UL112, which was subsequently found to function in immunomodulation [34]. We found that these HCMV genes which were correlated with DNA replication, gene expression regulation, and immunity showed high reads in CRC tissues.…”

Section: Discussionmentioning

confidence: 80%

Prevalence of human cytomegalovirus in colorectal cancer and viral gene expression profiles

Cai

Zhu

et al. 2020

Preprint

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Background Human cytomegalovirus (HCMV) infection plays a crucial role in the development and progression of cancer. However, the effect of HCMV on colorectal cancer (CRC) remains controversial. This study was performed to explore the pathogenesis of HCMV in CRC. Methods HCMV DNA was detected in 74 CRC and paired normal samples by PCR. HCMV IEA protein expression was confirmed in 717 CRC biopsies by immunohistochemistry. HCMV gene expression profiles (GEPs) were further analyzed in 5 CRC tissues by transcriptome sequencing. The associations of HCMV infection with clinical features and prognosis were also evaluated. Results The prevalence rates of HCMV in CRC tissues were 29.73% and 23.17% at the DNA and protein levels respectively, which was significantly higher than those in normal tissues (0%). Transcriptome sequencing to evaluate the GEPs revealed 119 HCMV genes in CRC tissues. The high reads of transcriptions were RNA2.7, RNA4.9, RNA5.0, RL5A, UL82, UL83, and UL70, which correlate with gene expression or regulation. Survival analysis showed that patients with CRC patients and pIEA(++) had longer overall survival (OS) than those with pIEA(+)s at the protein level. However, there was no correlation between pIEA expression and clinical features. Conclusions HCMV, a common virus found in CRC tissues, is related to the development and progression of CRC. GEP analysis revealed genes correlated with lytic infection. Additionally, genes functioning in gene expression or regulation showed high expression in CRC. We found that CRC patients with HCMV lytic infection have a better prognosis than those with non-HCMV infection. Here, we revealed features of the pathogenic mechanism and provide insight that may be useful for targeted treatment of CRC.

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Section: Discussionmentioning

confidence: 80%

Prevalence of human cytomegalovirus in colorectal cancer and viral gene expression profiles

Cai

Zhu

et al. 2020

Preprint

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“…Consistently, ERAP1 expression was significantly decreased by miR-UL112-5p overexpression only in fibroblasts from AA individuals, while fibroblasts from GG individuals did not show any alteration in RNA and protein levels [73]. Even more important, a significantly reduced HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV infection is negatively associated with adult-onset disorder [73].…”

Section: Eraps and Human Cytomegalovirus (Hcmv)mentioning

confidence: 88%

“…A more recent study focused onto another HCMV miRNA, miR-UL112-5p, whose function resembles the one played by miR-US4-1. Indeed, miR-UL112-5p directly targets the 3' UTR of ERAP1-A SNP variant, thus downregulating its mRNA expression and altering the presentation of many HCMV-derived antigenic peptides to CD8 + T cells [73]. Notably, the authors identified the rs17481334-G SNP variant, naturally occurring in the ERAP1 3' UTR, which disrupts the consensus sequence for HCMV miR-UL112-5p and, in turn, prevents ERAP1 targeting and degradation [73].…”

Section: Eraps and Human Cytomegalovirus (Hcmv)mentioning

confidence: 99%

“…Indeed, miR-UL112-5p directly targets the 3' UTR of ERAP1-A SNP variant, thus downregulating its mRNA expression and altering the presentation of many HCMV-derived antigenic peptides to CD8 + T cells [73]. Notably, the authors identified the rs17481334-G SNP variant, naturally occurring in the ERAP1 3' UTR, which disrupts the consensus sequence for HCMV miR-UL112-5p and, in turn, prevents ERAP1 targeting and degradation [73]. Consistently, ERAP1 expression was significantly decreased by miR-UL112-5p overexpression only in fibroblasts from AA individuals, while fibroblasts from GG individuals did not show any alteration in RNA and protein levels [73].…”

Section: Eraps and Human Cytomegalovirus (Hcmv)mentioning

confidence: 99%

“…Notably, the authors identified the rs17481334-G SNP variant, naturally occurring in the ERAP1 3' UTR, which disrupts the consensus sequence for HCMV miR-UL112-5p and, in turn, prevents ERAP1 targeting and degradation [73]. Consistently, ERAP1 expression was significantly decreased by miR-UL112-5p overexpression only in fibroblasts from AA individuals, while fibroblasts from GG individuals did not show any alteration in RNA and protein levels [73]. Even more important, a significantly reduced HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV infection is negatively associated with adult-onset disorder [73].…”

Section: Eraps and Human Cytomegalovirus (Hcmv)mentioning

confidence: 99%

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An Overview on ERAP Roles in Infectious Diseases

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Vicentini

Clerici

et al. 2020

Cells

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Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8 + T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches.

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Human cytomegalovirus microRNAs: strategies for immune evasion and viral latency

Sabbaghian,

Gheitasi,

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et al. 2024

Arch Virol

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

Cited by 33 publications

References 40 publications

Prevalence of human cytomegalovirus in colorectal cancer and viral gene expression profiles

Prevalence of human cytomegalovirus in colorectal cancer and viral gene expression profiles

An Overview on ERAP Roles in Infectious Diseases

Human cytomegalovirus microRNAs: strategies for immune evasion and viral latency

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