The Experts below are selected from a list of 2244 Experts worldwide ranked by ideXlab platform
Doriana Fruci - One of the best experts on this subject based on the ideXlab platform.
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erap1 and ERAP2 enzymes a protective shield for ras against covid 19
International Journal of Molecular Sciences, 2021Co-Authors: Silvia Damico, Patrizia Tempora, Valeria Lucarini, Ombretta Melaiu, Stefania Gaspari, Mattia Algeri, Doriana FruciAbstract:Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin-angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis.
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regulation of erap1 and ERAP2 genes and their disfunction in human cancer
Human Immunology, 2019Co-Authors: Mirco Compagnone, Loredana Cifaldi, Doriana FruciAbstract:The endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 are two multifunctional enzymes playing an important role in the biological processes requiring trimming of substrates, including the generation of major histocompatibility complex (MHC) class I binding peptides. In the absence of ERAP enzymes, the cells exhibit a different pool of peptides on their surface which can promote both NK and CD8+ T cell-mediated immune responses. The expression of ERAP1 and ERAP2 is frequently altered in tumors, as compared to their normal counterparts, but how this affects tumor growth and anti-tumor immune responses has been little investigated. This review will provide an overview of current knowledge on transcriptional and post-transcriptional regulations of ERAP enzymes, and will discuss the contribution of recent studies to our understanding of ERAP1 and ERAP2 role in cancer immunity.
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peptide trimming for mhc class i presentation by endoplasmic reticulum aminopeptidases
Methods of Molecular Biology, 2019Co-Authors: Mirco Compagnone, Doriana FruciAbstract:Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 have recently emerged as important players in regulating innate and adaptive immune responses by trimming peptide ligands for MHC class I molecules. Functional polymorphisms in ERAP1 and ERAP2 genes have been associated with predisposition to several diseases including autoimmune diseases, viral infections, and virally induced cancers. In this chapter, we describe two basic methods for monitoring peptide-trimming activity by ER aminopeptidases and screening potential chemical inhibitors.
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a role for naturally occurring alleles of endoplasmic reticulum aminopeptidases in tumor immunity and cancer pre disposition
Frontiers in Oncology, 2014Co-Authors: Efstratios Stratikos, Efthalia Zervoudi, Athanasios Stamogiannos, Doriana FruciAbstract:Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) are key components on the pathway that generates antigenic epitopes for presentation to cytotoxic T-lymphocytes (CTLs). Coding single nucleotide polymorphisms (SNPs) in these enzymes have been associated with pre-disposition to several major human diseases including inflammatory diseases with autoimmune etiology, viral infections, and virally induced cancer. The function of these enzymes has been demonstrated to affect CTL and natural killer cell responses toward healthy and malignant cells as well as the production of inflammatory cytokines. Recent studies have demonstrated that SNPs in ERAP1 and ERAP2 can affect their ability to generate or destroy antigenic epitopes and define the immunopeptidome. In this review, we examine the potential role of these enzymes and their polymorphic states on the generation of cytotoxic responses toward malignantly transformed cells. Given the current state-of-the-art, it is possible that polymorphic variation in these enzymes may contribute to the individual’s pre-disposition to cancer through altered generation or destruction of tumor antigens that can facilitate tumor immune evasion.
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endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class i associated autoimmune diseases
Tissue Antigens, 2014Co-Authors: Doriana Fruci, Paolo Romania, Valerio Dalicandro, Franco LocatelliAbstract:Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases.
Robert D. Inman - One of the best experts on this subject based on the ideXlab platform.
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serum cytokine receptors in ankylosing spondylitis relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms
The Journal of Rheumatology, 2010Co-Authors: Nigil Haroon, Florence W L Tsui, Hing Wo Tsui, Basil Chiu, Robert D. InmanAbstract:Objective. Endoplasmic reticulum aminopeptidase ( ERAP ) 1 is associated with ankylosing spondylitis (AS) and is known to be involved in the clipping of the cytokine receptors interleukin 1 receptor II (IL-1RII), IL-6Rα, and tumor necrosis factor receptor I (TNFRI). We studied the relationship of these serum cytokine receptors and their corresponding cytokines to markers of inflammation and polymorphisms in ERAP1 and ERAP2 in patients with AS. Methods. Sera from patients with AS were assayed for TNF-α, IL-1, IL-6, sTNFRI, sIL-1RII, and sIL-6Rα by ELISA. Genotyping was performed for 3 AS-associated nonsynonymous single-nucleotide polymorphisms in the ERAP1 gene [ rs27044(C/G) , rs10050860(C/T) , and rs30187(C/T) ] and 1 in the ERAP2 gene [ rs2549782(T/G) ]. The serum cytokine and receptor levels were compared between the different genotype groups and correlated to markers of inflammation and disease activity. Results. Eighty patients with AS (21 women) with a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 5.3 ± 2.4 were enrolled. There was a significant correlation of sTNFRI with C-reactive protein (CRP; R = 0.43, p < 0.001) and erythrocyte sedimentation rate (ESR; R = 0.30, p = 0.01) but not with BASDAI. Serum cytokine levels were undetectable in the majority of patients. There was no significant difference in serum cytokines or the soluble receptors between patients with the different ERAP1/ERAP2 polymorphisms and their haplotypes. Similarly, there was no relationship of the polymorphisms with the serum cytokine levels nor the cytokine-receptor ratio. Conclusion. Soluble TNFRI levels correlate with ESR and CRP in AS. The ERAP1 and ERAP2 polymorphisms associated with AS do not influence the serum cytokine receptor levels in patients with AS.
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serum cytokine receptors in ankylosing spondylitis relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms
The Journal of Rheumatology, 2010Co-Authors: Nigil Haroon, Florence W L Tsui, Hing Wo Tsui, Basil Chiu, Robert D. InmanAbstract:Objective. Endoplasmic reticulum aminopeptidase ( ERAP ) 1 is associated with ankylosing spondylitis (AS) and is known to be involved in the clipping of the cytokine receptors interleukin 1 receptor II (IL-1RII), IL-6Rα, and tumor necrosis factor receptor I (TNFRI). We studied the relationship of these serum cytokine receptors and their corresponding cytokines to markers of inflammation and polymorphisms in ERAP1 and ERAP2 in patients with AS. Methods. Sera from patients with AS were assayed for TNF-α, IL-1, IL-6, sTNFRI, sIL-1RII, and sIL-6Rα by ELISA. Genotyping was performed for 3 AS-associated nonsynonymous single-nucleotide polymorphisms in the ERAP1 gene [ rs27044(C/G) , rs10050860(C/T) , and rs30187(C/T) ] and 1 in the ERAP2 gene [ rs2549782(T/G) ]. The serum cytokine and receptor levels were compared between the different genotype groups and correlated to markers of inflammation and disease activity. Results. Eighty patients with AS (21 women) with a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 5.3 ± 2.4 were enrolled. There was a significant correlation of sTNFRI with C-reactive protein (CRP; R = 0.43, p < 0.001) and erythrocyte sedimentation rate (ESR; R = 0.30, p = 0.01) but not with BASDAI. Serum cytokine levels were undetectable in the majority of patients. There was no significant difference in serum cytokines or the soluble receptors between patients with the different ERAP1/ERAP2 polymorphisms and their haplotypes. Similarly, there was no relationship of the polymorphisms with the serum cytokine levels nor the cytokine-receptor ratio. Conclusion. Soluble TNFRI levels correlate with ESR and CRP in AS. The ERAP1 and ERAP2 polymorphisms associated with AS do not influence the serum cytokine receptor levels in patients with AS.
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endoplasmic reticulum aminopeptidases biology and pathogenic potential
Nature Reviews Rheumatology, 2010Co-Authors: Nigil Haroon, Robert D. InmanAbstract:Endoplasmic reticulum aminopeptidase 1 (ERAP1) and the closely related ERAP2 are involved in the final trimming of peptides within the endoplasmic reticulum for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 was found to be associated with ankylosing spondylitis (AS) in a genome-wide association study of nonsynonymous single nucleotide polymorphisms, and this association has been confirmed in several studies. An ERAP1/ERAP2 haplotype has also been reported to be associated with familial AS. ERAP1 and ERAP2 could carry out several potential roles in the pathogenesis of AS. ERAP1-deficient mice show a considerable alteration in the level and repertoire of peptides presented by MHC class I molecules. Furthermore, ERAP1 has been shown to be involved in shedding cytokine receptors. Both of these functions require further analysis to better understand the exact role of ERAP1 in AS.
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association of an erap1 ERAP2 haplotype with familial ankylosing spondylitis
Annals of the Rheumatic Diseases, 2010Co-Authors: Florence W L Tsui, Hing Wo Tsui, Basil Chiu, Nigil Haroon, Robert D. Inman, John D Reveille, Proton RahmanAbstract:Objectives To assess whether there is excess transmission of alleles from the ERAP1 ERAP2 locus in families with ankylosing spondylitis (AS). Methods 199 multiplex families with AS with four non-synonymous single nucleotide polymorphisms (SNPs), three in the endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) gene ( rs27044 , rs10050860 and rs30187 ) and one in the endoplasmic reticulum aminopeptidase 2 ( ERAP2 ) gene ( rs2549782 ), were genotyped and family-based association analyses were performed. Results Family-based association testing (FBAT –e; empirical variance option) analysis showed that ERAP1 rs30187[T] was associated with AS (additive model: p = 0.02; dominant model: p=0.007). Haplotype permutation tests (HBAT-p) showed that a haplotype in the ERAP1 and ERAP2 locus ( rs27044[G] rs30187[T] rs2549782[T] ) was significantly associated with AS (two-sided p value by permutation test 0.009 for additive and 0.008 for dominant model, respectively). Conclusion This study shows that one ERAP1 SNP and a haplotype in the ERAP1 and ERAP2 locus are associated with familial AS.
Nigil Haroon - One of the best experts on this subject based on the ideXlab platform.
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endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis
Rheumatology, 2015Co-Authors: Tony J Kenna, Nigil Haroon, Philip RobinsonAbstract:There has been significant progress in our understanding of the pathogenesis of AS. The advent of genome-wide association studies has increased the known loci associated with AS to more than 40. The endoplasmic reticulum resident aminopeptidases (ERAP) 1 and 2 were identified in this manner and are of particular interest. There appears to be a genetic as well as a functional interaction of ERAP1 and 2 with HLA-B27 based on the known functions of these molecules. Recent studies on the structure, immunological effects and the peptide-trimming properties of ERAP 1 and 2 have helped to provide insight into their pathogenic potential in AS. In this review, we explore the role of ERAP 1 and 2 in the pathogenesis of AS.
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endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis
Faculty of Health; Institute of Health and Biomedical Innovation, 2015Co-Authors: Tony J Kenna, Nigil Haroon, Philip RobinsonAbstract:This article is 'Free to read' on journal website. There has been significant progress in our understanding of the pathogenesis of AS. The advent of genome-wide association studies has increased the known loci associated with AS to more than 40. The endoplasmic reticulum resident aminopeptidases (ERAP) 1 and 2 were identified in this manner and are of particular interest. There appears to be a genetic as well as a functional interaction of ERAP1 and 2 with HLA-B27 based on the known functions of these molecules. Recent studies on the structure, immunological effects and the peptide-trimming properties of ERAP 1 and 2 have helped to provide insight into their pathogenic potential in AS. In this review, we explore the role of ERAP 1 and 2 in the pathogenesis of AS. © The Author 2015.
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serum cytokine receptors in ankylosing spondylitis relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms
The Journal of Rheumatology, 2010Co-Authors: Nigil Haroon, Florence W L Tsui, Hing Wo Tsui, Basil Chiu, Robert D. InmanAbstract:Objective. Endoplasmic reticulum aminopeptidase ( ERAP ) 1 is associated with ankylosing spondylitis (AS) and is known to be involved in the clipping of the cytokine receptors interleukin 1 receptor II (IL-1RII), IL-6Rα, and tumor necrosis factor receptor I (TNFRI). We studied the relationship of these serum cytokine receptors and their corresponding cytokines to markers of inflammation and polymorphisms in ERAP1 and ERAP2 in patients with AS. Methods. Sera from patients with AS were assayed for TNF-α, IL-1, IL-6, sTNFRI, sIL-1RII, and sIL-6Rα by ELISA. Genotyping was performed for 3 AS-associated nonsynonymous single-nucleotide polymorphisms in the ERAP1 gene [ rs27044(C/G) , rs10050860(C/T) , and rs30187(C/T) ] and 1 in the ERAP2 gene [ rs2549782(T/G) ]. The serum cytokine and receptor levels were compared between the different genotype groups and correlated to markers of inflammation and disease activity. Results. Eighty patients with AS (21 women) with a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 5.3 ± 2.4 were enrolled. There was a significant correlation of sTNFRI with C-reactive protein (CRP; R = 0.43, p < 0.001) and erythrocyte sedimentation rate (ESR; R = 0.30, p = 0.01) but not with BASDAI. Serum cytokine levels were undetectable in the majority of patients. There was no significant difference in serum cytokines or the soluble receptors between patients with the different ERAP1/ERAP2 polymorphisms and their haplotypes. Similarly, there was no relationship of the polymorphisms with the serum cytokine levels nor the cytokine-receptor ratio. Conclusion. Soluble TNFRI levels correlate with ESR and CRP in AS. The ERAP1 and ERAP2 polymorphisms associated with AS do not influence the serum cytokine receptor levels in patients with AS.
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serum cytokine receptors in ankylosing spondylitis relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms
The Journal of Rheumatology, 2010Co-Authors: Nigil Haroon, Florence W L Tsui, Hing Wo Tsui, Basil Chiu, Robert D. InmanAbstract:Objective. Endoplasmic reticulum aminopeptidase ( ERAP ) 1 is associated with ankylosing spondylitis (AS) and is known to be involved in the clipping of the cytokine receptors interleukin 1 receptor II (IL-1RII), IL-6Rα, and tumor necrosis factor receptor I (TNFRI). We studied the relationship of these serum cytokine receptors and their corresponding cytokines to markers of inflammation and polymorphisms in ERAP1 and ERAP2 in patients with AS. Methods. Sera from patients with AS were assayed for TNF-α, IL-1, IL-6, sTNFRI, sIL-1RII, and sIL-6Rα by ELISA. Genotyping was performed for 3 AS-associated nonsynonymous single-nucleotide polymorphisms in the ERAP1 gene [ rs27044(C/G) , rs10050860(C/T) , and rs30187(C/T) ] and 1 in the ERAP2 gene [ rs2549782(T/G) ]. The serum cytokine and receptor levels were compared between the different genotype groups and correlated to markers of inflammation and disease activity. Results. Eighty patients with AS (21 women) with a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 5.3 ± 2.4 were enrolled. There was a significant correlation of sTNFRI with C-reactive protein (CRP; R = 0.43, p < 0.001) and erythrocyte sedimentation rate (ESR; R = 0.30, p = 0.01) but not with BASDAI. Serum cytokine levels were undetectable in the majority of patients. There was no significant difference in serum cytokines or the soluble receptors between patients with the different ERAP1/ERAP2 polymorphisms and their haplotypes. Similarly, there was no relationship of the polymorphisms with the serum cytokine levels nor the cytokine-receptor ratio. Conclusion. Soluble TNFRI levels correlate with ESR and CRP in AS. The ERAP1 and ERAP2 polymorphisms associated with AS do not influence the serum cytokine receptor levels in patients with AS.
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endoplasmic reticulum aminopeptidases biology and pathogenic potential
Nature Reviews Rheumatology, 2010Co-Authors: Nigil Haroon, Robert D. InmanAbstract:Endoplasmic reticulum aminopeptidase 1 (ERAP1) and the closely related ERAP2 are involved in the final trimming of peptides within the endoplasmic reticulum for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 was found to be associated with ankylosing spondylitis (AS) in a genome-wide association study of nonsynonymous single nucleotide polymorphisms, and this association has been confirmed in several studies. An ERAP1/ERAP2 haplotype has also been reported to be associated with familial AS. ERAP1 and ERAP2 could carry out several potential roles in the pathogenesis of AS. ERAP1-deficient mice show a considerable alteration in the level and repertoire of peptides presented by MHC class I molecules. Furthermore, ERAP1 has been shown to be involved in shedding cytokine receptors. Both of these functions require further analysis to better understand the exact role of ERAP1 in AS.
Peter Van Endert - One of the best experts on this subject based on the ideXlab platform.
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trimming of mhc class i ligands by erap aminopeptidases
Methods of Molecular Biology, 2019Co-Authors: Mirjana Weimershaus, Irini Evnouchidou, Peter Van Endert, Marlene BouvierAbstract:Studies over the last decade on characterization of the major histocompatibility complex (MHC) class I antigen presentation pathway have highlighted the importance of antigen processing, peptide transport, peptide trimming, and peptide selection as key stages for the development of optimal peptide repertoires that are presented by MHC class I molecules to cytotoxic T lymphocytes (CTLs). The study of these stages and how they are regulated, is fundamental for progress in understanding the adaptive immune system. Here we describe an in vitro assay monitoring peptide trimming by the human endoplasmic reticulum amino peptidases 1 (ERAP1) and ERAP2 (ERAPs) as a tool to characterize trimming events and gain a better understanding of the role and function of ERAPs in peptide repertoire development. Specifically, our assay allows for monitoring trimming of free but also of MHC I-bound peptides which may reflect the physiological situation best.
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erap1 ERAP2 dimers trim mhc i bound precursor peptides implications for understanding peptide editing
Scientific Reports, 2016Co-Authors: Hanna Chen, Mirjana Weimershaus, Irini Evnouchidou, Peter Van Endert, Marlene BouvierAbstract:The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biology of antigen presentation. To date, the molecular context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a molecular mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens.
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3 4 diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of m1 aminopeptidases with immune regulating properties
Journal of Medicinal Chemistry, 2015Co-Authors: Athanasios Papakyriakou, Efthalia Zervoudi, Emmanuel A Theodorakis, Dionisios Vourloumis, Peter Van Endert, Francoisxavier Mauvais, Sofia Tsoukalidou, Georgia Sfyroera, Dimitrios C Mastellos, Efstratios StratikosAbstract:Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.
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erap1 ERAP2 dimerization increases peptide trimming efficiency
Journal of Immunology, 2014Co-Authors: Irini Evnouchidou, Loredana Saveanu, Mirjana Weimershaus, Peter Van EndertAbstract:The endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 play a critical role in the production of final epitopes presented by MHC class I molecules. Formation of heterodimers by ERAP1 and ERAP2 has been proposed to facilitate trimming of epitope precursor peptides, but the effects of dimerization on ERAP function remain unknown. In this study, we produced stabilized ERAP1-ERAP2 heterodimers and found that they produced several mature epitopes more efficiently than a mix of the two enzymes unable to dimerize. Physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity. Thus, by bringing the two enzymes in proximity and by producing allosteric effects on ERAP1, dimerization of ERAP1/2 creates complexes with superior peptide-trimming efficacy. Such complexes are likely to enhance Ag presentation by cells displaying coordinated expression of the two enzymes.
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distinct molecular mechanisms leading to deficient expression of er resident aminopeptidases in melanoma
Cancer Immunology Immunotherapy, 2010Co-Authors: Esther Kamphausen, Peter Van Endert, Christiane Kellert, Tarish Abbas, Nadja Akkad, Stefan Tenzer, Graham Pawelec, Hansjoerg Schild, Barbara SeligerAbstract:Immune surveillance of tumour cells by CD8+ cytotoxic T cells plays a key role in the establishment and control of an anti-tumour response. This process requires the generation of antigenic peptides, which are largely produced by the proteasome in combination with other proteases located in either the cytoplasm and/or the endoplasmic reticulum (ER). The ER-resident aminopeptidases ERAP1 and ERAP2 trim or even destroy HLA class I-binding peptides thereby shaping the peptide repertoire presented for T cell recognition. So far there exists limited information about the expression pattern of ERAP1 and/or ERAP2 in human tumours of distinct histotypes. Therefore, the expression profiles and modes of regulation of both aminopeptidases were determined in a large series of melanoma cell lines. A heterogeneous expression ranging from high to reduced or even total loss of ERAP1 and/or ERAP2 mRNA and/or protein expression was detected, which often could be induced/upregulated by interferon-γ treatment. The observed altered ERAP1 and/or ERAP2 expression and activity levels were either mediated by sequence alterations affecting the promoter or enzymatic activities, leading to either transcriptional and/or post-transcriptional downregulation mechanisms or limited or excessive processing activities, which both might have an impact on the antigenic peptide repertoire presented on HLA class I molecules.
Efstratios Stratikos - One of the best experts on this subject based on the ideXlab platform.
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ERAP2 facilitates a subpeptidome of birdshot uveitis associated hla a29
bioRxiv, 2020Co-Authors: Wouter J Venema, Efstratios Stratikos, Sanne Hiddingh, Anneke Den I Hollander, A. De ,mulder, Joke H De Boer, Frans H J Claas, Siranush Sarkizova, Lars T Van Der Veken, George M C JanssenAbstract:Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labelled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.
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generation of sars cov 2 s1 spike glycoprotein putative antigenic epitopes in vitro by intracellular aminopeptidases
Journal of Proteome Research, 2020Co-Authors: George Stamatakis, George Panayotou, Martina Samiotaki, Anastasia Mpakali, Efstratios StratikosAbstract:Presentation of antigenic peptides by MHCI is central to cellular immune responses against viral pathogens. While adaptive immune responses versus SARS-CoV-2 can be of critical importance to both recovery and vaccine efficacy, how protein antigens from this pathogen are processed to generate antigenic peptides is largely unknown. Here, we analyzed the proteolytic processing of overlapping precursor peptides spanning the entire sequence of the S1 spike glycoprotein of SARS-CoV-2, by three key enzymes that generate antigenic peptides, aminopeptidases ERAP1, ERAP2, and IRAP. All enzymes generated shorter peptides with sequences suitable for binding onto HLA alleles, but with distinct specificity fingerprints. ERAP1 was the most efficient in generating peptides 8-11 residues long, the optimal length for HLA binding, while IRAP was the least efficient. The combination of ERAP1 with ERAP2 greatly limited the variability of peptide sequences produced. Less than 7% of computationally predicted epitopes were found to be produced experimentally, suggesting that aminopeptidase processing may constitute a significant filter to epitope presentation. These experimentally generated putative epitopes could be prioritized for SARS-CoV-2 immunogenicity studies and vaccine design. We furthermore propose that this in vitro trimming approach could constitute a general filtering method to enhance the prediction robustness for viral antigenic epitopes.
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the differential expression of erap1 ERAP2 and immune cell activation in pre eclampsia
Frontiers in Immunology, 2020Co-Authors: Kimberly Seamon, Efstratios Stratikos, Lesia O Kurlak, Michelle Warthan, Jerome F Strauss, Hiten D Mistry, Eun D LeeAbstract:Pre-eclampsia (PE) is a disorder of pregnancy, often leading to serious and fatal complications. Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1/ERAP2) are present in the placenta. They are involved in processes regulating blood pressure, angiogenesis, cytokine receptor shedding, and immune recognition. Previous studies have associated both ERAP1/ERAP2 genetic variants with PE, although the underlying mechanisms remain unknown. Less is known about the roles for these enzymes in early placentation, which could be a contributory factor to PE. To ascertain whether ERAP1/ERAP2 change in PE and whether such a change is present before PE is clinically diagnosed, we analyzed mRNA and ERAP1/2 protein expression in the placenta in the early first trimester (8-14 weeks) and at delivery in normotensive or PE women (n = 12/group). Gene expression was analyzed using qPCR, and protein expression and localization were assessed by immunohistochemistry. Additionally, we profiled peripheral immune cells from normotensive and PE (n = 5/group) women for activation and expression of cytotoxic markers using flow cytometry to investigate a possible correlation with placental expression of ERAP1/2. Finally, we characterized the cytokines released from immune cells isolated from normotensive women and those with PE, stimulated ex vivo by JEG-3 trophoblast cells. The ERAP1 protein was significantly upregulated in first trimester placentae compared to placentae at delivery from both normotensive and PE women (p < 0.05): expression of placental ERAP1 protein was also relatively higher in normotensive than PE women. Although the protein expression of both ERAP1/ERAP2 was significantly lower in women with PE compared to normotensive controls (p < 0.05), ERAP2 protein expression remained unchanged in normotensive women at delivery compared to expression in the first trimester. Flow cytometry analysis revealed an increase in activation and cytotoxic natural killer (NK) cells in peripheral blood of PE compared to normotensive women. Intriguingly, there was a notable difference in cytokine release from the activated immune cells when further stimulated by trophoblast cells. The immune cells from PE released elevated expressions of interleukin (IL)-2, IL-4, and most notably, pro-inflammatory IL-13 and IL-17α, inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to normal peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that differential lymphocyte activation could be associated with altered ERAP1/ERAP2 expression.
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intracellular antigen processing by ERAP2 molecular mechanism and roles in health and disease
Human Immunology, 2019Co-Authors: Jose Lopez A De Castro, Efstratios StratikosAbstract:Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) is an intracellular enzyme localized in the ER that has been shown to play roles in the generation of peptides that serve as ligands for MHC class I (MHC-1) molecules. Although ERAP2 has been primarily described as an accessory and complementary enzyme to the homologous ERAP1, several lines of evidence during the last few years suggest that it can play distinct and important roles in processing antigenic peptides and influencing cellular cytotoxic immune responses. Such emerging evidence has been shaping ERAP2 as a potentially tractable target for regulating select autoimmune and anti-cancer responses for therapeutic purposes. Here, we review the state-of-the-art knowledge on the role of ERAP2 in antigen processing, its structure and molecular mechanism, influence on shaping MHC-I-bound immunopeptidomes and its involvement in disease pathogenesis.
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the role of conformational dynamics in antigen trimming by intracellular aminopeptidases
Frontiers in Immunology, 2017Co-Authors: Athanasios Papakyriakou, Efstratios StratikosAbstract:Antigenic peptides presented by the major histocompatibility complex class I (MHC-I) molecules for recognition by cytotoxic T-lymphocytes are processed by members of the oxytocinase sub-family of M1 aminopeptidases ERAP1, ERAP2 and IRAP. These three homologous zinc metallopeptidases trim N-terminally extended precursor antigenic peptides down to the correct length for loading onto the MHC-I but can also destroy some antigenic peptides by over-trimming, therefore influencing the antigenic peptide repertoire and immunodominance hierarchy. Polymorphic variation has been found to affect their trimming function and predispose to human disease in complex and poorly understood patterns. Structural and biochemical analysis have pointed towards a complicated trimming mechanism that involves a major conformational transition during each catalytic cycle. Here, we provide an overview of current knowledge on the structure and mechanism of action of those enzymes with a focus on the proposed key role of conformational dynamics in their function.