Regulation of ERAP1 and ERAP2 genes and their disfunction in human cancer

Compagnone, Mirco; Cifaldi, Loredana; Fruci, Doriana

doi:10.1016/j.humimm.2019.02.014

Cited by 59 publications

(49 citation statements)

References 81 publications

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“…In order to characterize the underlying regulatory mechanisms, we generated a luciferase reporter construct to assess the transcriptional regulation of the ERAP1 gene by introducing the ERAP1 promoter region (-1325/+60) (35) upstream a luciferase encoding sequence ( Figure 2D). Following transfection of the reporter construct in EndoC-βH1 and stress treatment induction, a 3-fold increase in light emission after IFNɣ/IL1β treatment was observed, which confirms the transcriptional regulation by IFNɣ (36). However, the absence of transcriptional activation of the ERAP1 promoter after thapsigargin treatment in our assay, suggested additional regulatory mechanisms controlling ERAP1 gene expression during ER stress.…”

Section: Erap1 Is Upregulated By Inflammation and Endoplasmic Reticulsupporting

confidence: 76%

β-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

et al. 2020

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The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CTL-mediated beta-cell destruction in Type 1 Diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in recent onset T1D patients. While the combined action of signal peptide peptidase and endoplasmic reticulum aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human beta cells that ER stress regulates ERAP1 gene expression at post-transcriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of beta cells to the immune system and position the IRE1α/miR-17 pathway as a central component in beta cell destruction processes and as potential target for the treatment of autoimmune T1D.

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Section: Erap1 Is Upregulated By Inflammation and Endoplasmic Reticulsupporting

confidence: 76%

β-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

et al. 2020

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“…Specifically, deletion of ERAP1 in mouse tumors was reported to increase the efficiency of anti-PD-1 immunotherapy. 52,53) Furthermore, low levels of ERAP2 were found to be associated with improved response to anti-PD-L1 in human patients with bladder cancer. 54) On the other hand, besides acting as a processing enzyme, ERAP1 secreted into the extracellular milieu activates immune cells such as macrophages and NK cells, and stimulates the production of pro-inflammatory cytokines.…”

Section: Resultsmentioning

confidence: 99%

“…4) It is now well recognized that ERAP1 is primarily an antigenic peptide-processing enzyme located in the lumen of endoplasmic reticulum (ER-lumen), and involved in several autoimmune and inflammatory diseases. [5][6][7][8] However, there are additional activities of ERAP1 that have not been well documented to date. Here, we summarize multiple functions of ERAP1 enzyme outside ER-lumen.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Tsujimoto

Aoki

Ohnishi

et al. 2020

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptideprocessing enzyme, specifically emphasizing on its secretory form.

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“…ERAP1 is a member of the oxytocinase subfamily of M1 zinc metallopeptidases with which it shares two key sequence motifs essential for their enzymatic activity, HEXXH(X) 18 E zinc-binding and GAMEN substrate recognition sequences [31]. In humans, the ERAP1 gene is located on chromosome 5q15 in a 167 Kb segment in the opposite direction of its homologous ERAP2 from which it arose by gene duplication [32] (Figure 2).…”

Section: Biological Functions Of Erap1mentioning

confidence: 99%

“…ERAP1 plays an important role in various biological processes that require the trimming of amino acid residues at the N-terminal polypeptide level by picking the substrates based on both N-terminus and internal sequences [31]. Hydrophobic amino acid residues (with the exception of proline) and peptides with a hydrophobic C-terminus are preferentially cleaved by ERAP1.…”

Section: Biological Functions Of Erap1mentioning

confidence: 99%

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

D’Amico

Tempora

Lucarini

et al. 2020

IJMS

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Human cytomegalovirus (HCMV) is a β-herpesvirus that causes serious problems in people with a compromised immune system, whereas it coexists asymptomatically within the host with a healthy immune system. Like other viruses, HCMV has adopted multiples strategies to manipulate the host’s immune responses. Among them, expression of viral microRNAs (miRNAs) is one of the most intriguing. HCMV miR-UL112-5p and miR-US4-1 have been found to contribute to immune evasion by targeting the endoplasmic reticulum aminopeptidase 1 (ERAP1), a highly polymorphic key component of antigen processing. The current incomplete picture on the interplay between viral miRNAs and host immunity implies the need to better characterize the host genetic determinants. Naturally occurring single nucleotide polymorphisms (SNPs) within the miRNA binding sites of target genes may affect miRNA–target interactions. In this review, we focus on the relevance of 3′ untranslated region (3′UTR) ERAP1 SNPs within miRNA binding sites in modulating miRNA–mRNA interactions and the possible consequent individual susceptibility to HCMV infection. Moreover, we performed an in silico analysis using different bioinformatic algorithms to predict ERAP1 variants with a putative powerful biological function. This evidence provides a basis to deepen the knowledge on how 3′UTR ERAP1 variants may alter the mechanism of action of HCMV miRNAs, in order to develop targeted antiviral therapies.

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Regulation of ERAP1 and ERAP2 genes and their disfunction in human cancer

Cited by 59 publications

References 81 publications

β-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

β-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Impact of Natural Occurring ERAP1 Single Nucleotide Polymorphisms within miRNA-Binding Sites on HCMV Infection

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