DOCSLIB.ORG

ERAP1 Biology and Assessment in Ankylosing Spondylitis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ERAP1 Biology and Assessment in Ankylosing Spondylitis LETTER LETTER ERAP1 biology and assessment in Ankylosing Spondylitis We read with interest the work of Reeves preferences, form heterodimers, and work ences in the aminopeptidase pathway in mice et al. on endoplasmic reticulum amino- in concert to trim peptides. This difference and humans. Reeves et al.’s(1)conclusions peptidase 1 (ERAP1) haplotypes found in means that extrapolation of murine ER ami- are not robust because they fail to meet both Ankylosing Spondylitis (AS), and have sev- nopeptidase research to humans requires these criteria. eral concerns about the study and its con- a high degree of caution. For example, Reeves clusions (1). et al. (1) state that ERAP1-deficient cells have Philip C. Robinsona,1 and Reeves et al. (1) claim, on the basis of se- 20–30% reduction in MHC class I presenta- Matthew A. Brownb quence data from 19 cases and 17 controls, tion, citing previously published data from aCentre for Neurogenetics and Statistical that two haplotypes (*002 and *011) have ERAAP-deficient mice (2). In contrast, in Genomics, Queensland Brain Institute, reduced frequency in cases and two (*001 humans ERAP1 knockdown can reduce de- University of Queensland, Brisbane, QLD and *005) have increased frequency. Two of struction of MHC ligands and increase the 4072, Australia; and bUniversity of these four haplotypes actually have no statis- surface expression of MHC class I molecules Queensland Diamantina Institute, tically significant difference (Fisher’sexact (3), ERAP2 deficiency reduces surface MHC P values > 0.05 for *005 and *011), and class I presentation (4), and the effect of Translational Research Institute, Princess one is marginally associated (P = 0.045, hap- combined ERAP1 and ERAP2 deficiency in Alexandra Hospital, Brisbane, QLD 4102, lotype *001), and not associated if appropri- humans, analogous to ERAAP deficiency Australia ate levels of multiple comparison correction in mice, is unknown. are applied. With the exception of the studies Reeves et al. (1) conclude that ERAP1 var- 1 Reeves E, Colebatch-Bourn A, Elliott T, Edwards CJ, James E (2014) using the ERAP1 KO 293T cell line, all of the iation is involved in AS through effects on Functionally distinct ERAP1 allotype combinations distinguish findingsofthestudyarebasedonthecon- antigen trimming. However, the in vitro individuals with Ankylosing Spondylitis. Proc Natl Acad Sci USA clusion that there is differential association of model used in this study does not directly 111(49):17594–17599. 2 Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N (2006) the ERAP1 haplotypes with AS; given that assay trimming function, but rather the entire The aminopeptidase ERAAP shapes the peptide repertoire displayed that has not been demonstrated, these con- MHC class I processing and presentation by major histocompatibility complex class I molecules. Nat Immunol clusions are not robust. pathway. The observation that AS-associated 7(1):103–112. 3 York IA, et al. (2002) The ER aminopeptidase ERAP1 enhances or As Reeves et al. (1) themselves point out, ERAP1 haplotypes are associated with re- limits antigen presentation by trimming epitopes to 8-9 residues. Nat they also observe a risk association with duced MHC–protein complex levels can be Immunol 3(12):1177–1184. rs30187, in contrast to the findings of multi- explained by either decreased trimming to 4 Andrés AM, et al.; NISC Comparative Sequencing Program (2010) Balancing selection maintains a form of ERAP2 that undergoes ple association studies in both Asian- and produce ligands or by destruction of ligands nonsense-mediated decay and affects antigen presentation. PLoS European-descent populations. (3). In vitro models measuring trimming Genet 6(10):e1001157. Reeves et al. (1) investigate the effects of function directly show that SNPs associated 5 Evans DM, et al.; Spondyloarthritis Research Consortium of Canada (SPARCC); Australo-Anglo-American Spondyloarthritis ERAP1 variation, transfecting human ERAP1 with increased risk of AS are associated Consortium (TASC); Wellcome Trust Case Control Consortium 2 (and N-terminally extended peptide) into with increased trimming velocity of human (WTCCC2) (2011) Interaction between ERAP1 and HLA-B27 in “Erap1-deficient” murine cells. However, ERAP1 (5). ankylosing spondylitis implicates peptide handling in the mechanism Nat Genet – mice have only one identified ER resident Further studies of the role of aminopepti- for HLA-B27 in disease susceptibility. 43(8):761 767. aminopeptidase (termed “ERAAP” for ER dase variants in human disease should be aminopeptidase associated with antigen pro- based on firm data as to the direction of Author contributions: P.C.R. and M.A.B. wrote the paper. cessing, not “Erap1”), not two (ERAP1 genetic association of the variants or haplo- The authors declare no conflict of interest. and ERAP2)asinhumans.Inhumans, types studied, and if using experimental 1To whom correspondence should be addressed. Email: philip. ERAP1 and ERAP2 have different peptide animals, take into account the major differ- [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1501475112 PNAS Early Edition | 1of1 Downloaded by guest on October 3, 2021.
Load more

Recommended publications
  • An Overview on ERAP Roles in Infectious Diseases
    cells Review An Overview on ERAP Roles in Infectious Diseases 1,2, , 1, 2,3 1 Irma Saulle * y, Chiara Vicentini y, Mario Clerici and Mara Biasin 1 Cattedra di Immunologia, Dipartimento di Scienze Biomediche e Cliniche L. Sacco”, Università degli Studi di Milano, 20157 Milan, Italy; [email protected] (C.V.); [email protected] (M.B.) 2 Cattedra di Immunologia, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti Università degli Studi di Milano, 20122 Milan, Italy; [email protected] 3 IRCCS Fondazione Don Carlo Gnocchi, 20157 Milan, Italy * Correspondence: [email protected]; Tel.: +39-0250319679 These authors equally contributed to this work. y Received: 13 February 2020; Accepted: 12 March 2020; Published: 14 March 2020 Abstract: 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.
    [Show full text]
  • Influence of ERAP1 and ERAP2 Gene Polymorphisms on Disease
    Human Immunology 80 (2019) 325–334 Contents lists available at ScienceDirect Human Immunology journal homepage: www.elsevier.com/locate/humimm Influence of ERAP1 and ERAP2 gene polymorphisms on disease T susceptibility in different populations ⁎ Yufeng Yaoa,b, Nannan Liua, Ziyun Zhoua, Li Shia,b, a Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming 650118, China ARTICLE INFO ABSTRACT Keywords: The endoplasmic reticulum aminopeptidases (ERAPs), ERAP1 and ERAP2, makes a role in shaping the HLA class ERAP1 I peptidome by trimming peptides to the optimal size in MHC-class I-mediated antigen presentation and edu- ERAP2 cating the immune system to differentiate between self-derived and foreign antigens. Association studies have Polymorphism shown that genetic variations in ERAP1 and ERAP2 genes increase susceptibility to autoimmune diseases, in- Disease association fectious diseases, and cancers. Both ERAP1 and ERAP2 genes exhibit diverse polymorphisms in different po- Population genetic background pulations, which may influence their susceptibly to the aforementioned diseases. In this article, we reviewthe distribution of ERAP1 and ERAP2 gene polymorphisms in various populations; discuss the risk or protective influence of these gene polymorphisms in autoimmune diseases, infectious diseases, and cancers; and highlight how ERAP genetic variations can influence disease associations. 1. ERAP gene introduction to CD8+ T cells [1,2]. ERAPs have been found to trim peptides to the optimal size for MHC-I binding [3,4] but can also over-trim and destroy 1.1. ERAPs play an important role in the antigen presentation process MHC-I ligands.
    [Show full text]
  • Sex-Specific Differences in Endoplasmic Reticulum Aminopeptidase 1 Modulation Influence Blood Pressure and Renin-Angiotensin System Responses
    Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses Sanjay Ranjit, … , Gordon H. Williams, Jose R. Romero JCI Insight. 2019;4(21):e129615. https://doi.org/10.1172/jci.insight.129615. Research Article Endocrinology Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/–) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/– mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/– mice had normal ALDO levels but lacked normal renovascular responses. In humans,E RAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels. Find the latest version: https://jci.me/129615/pdf RESEARCH ARTICLE Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin- angiotensin system responses Sanjay Ranjit, Jian Yao Wong, Jia W.
    [Show full text]
  • Genome-Wide Association and Gene Enrichment Analyses of Meat Sensory Traits in a Crossbred Brahman-Angus
    Proceedings of the World Congress on Genetics Applied to Livestock Production, 11. 124 Genome-wide association and gene enrichment analyses of meat tenderness in an Angus-Brahman cattle population J.D. Leal-Gutíerrez1, M.A. Elzo1, D. Johnson1 & R.G. Mateescu1 1 University of Florida, Department of Animal Sciences, 2250 Shealy Dr, 32608 Gainesville, Florida, United States. [email protected] Summary The objective of this study was to identify genomic regions associated with meat tenderness related traits using a whole-genome scan approach followed by a gene enrichment analysis. Warner-Bratzler shear force (WBSF) was measured on 673 steaks, and tenderness and connective tissue were assessed by a sensory panel on 496 steaks. Animals belong to the multibreed Angus-Brahman herd from University of Florida and range from 100% Angus to 100% Brahman. All animals were genotyped with the Bovine GGP F250 array. Gene enrichment was identified in two pathways; the first pathway is involved in negative regulation of transcription from RNA polymerase II, and the second pathway groups several cellular component of the endoplasmic reticulum membrane. Keywords: tenderness, gene enrichment, regulation of transcription, cell growth, cell proliferation Introduction Identification of quantitative trait loci (QTL) for any complex trait, including meat tenderness, is the first most important step in the process of understanding the genetic architecture underlying the phenotype. Given a large enough population and a dense coverage of the genome, a genome-wide association study (GWAS) is usually successful in uncovering major genes and QTLs with large and medium effect on these type of traits. Several GWA studies on Bos indicus (Magalhães et al., 2016; Tizioto et al., 2013) or crossbred beef cattle breeds (Bolormaa et al., 2011b; Hulsman Hanna et al., 2014; Lu et al., 2013) were successful at identifying QTL for meat tenderness; and most of them include the traditional candidate genes µ-calpain and calpastatin.
    [Show full text]
  • The MER41 Family of Hervs Is Uniquely Involved in the Immune-Mediated Regulation of Cognition/Behavior-Related Genes
    bioRxiv preprint doi: https://doi.org/10.1101/434209; this version posted October 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The MER41 family of HERVs is uniquely involved in the immune-mediated regulation of cognition/behavior-related genes: pathophysiological implications for autism spectrum disorders Serge Nataf*1, 2, 3, Juan Uriagereka4 and Antonio Benitez-Burraco 5 1CarMeN Laboratory, INSERM U1060, INRA U1397, INSA de Lyon, Lyon-Sud Faculty of Medicine, University of Lyon, Pierre-Bénite, France. 2 University of Lyon 1, Lyon, France. 3Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France. 4Department of Linguistics and School of Languages, Literatures & Cultures, University of Maryland, College Park, USA. 5Department of Spanish, Linguistics, and Theory of Literature (Linguistics). Faculty of Philology. University of Seville, Seville, Spain * Corresponding author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/434209; this version posted October 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ABSTRACT Interferon-gamma (IFNa prototypical T lymphocyte-derived pro-inflammatory cytokine, was recently shown to shape social behavior and neuronal connectivity in rodents. STAT1 (Signal Transducer And Activator Of Transcription 1) is a transcription factor (TF) crucially involved in the IFN pathway.
    [Show full text]
  • Identification of ANKDD1B Variants in an Ankylosing Spondylitis Pedigree and a Sporadic Patient
    Tan et al. BMC Medical Genetics (2018) 19:111 https://doi.org/10.1186/s12881-018-0622-9 RESEARCH ARTICLE Open Access Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient Zhiping Tan1,2*, Hui Zeng1,2, Zhaofa Xu3, Qi Tian3, Xiaoyang Gao3, Chuanman Zhou3, Yu Zheng3, Jian Wang1,2, Guanghui Ling4, Bing Wang5, Yifeng Yang1,2 and Long Ma3* Abstract Background: Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis. Methods: We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient. Results: We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort.
    [Show full text]
  • Structural Insights Into the Molecular Ruler Mechanism of the Endoplasmic Reticulum Aminopeptidase ERAP1
    Structural insights into the molecular ruler mechanism of the endoplasmic reticulum SUBJECT AREAS: STRUCTURAL BIOLOGY aminopeptidase ERAP1 IMMUNOLOGY Amit Gandhi1, Damodharan Lakshminarasimhan1, Yixin Sun2 & Hwai-Chen Guo1 PROTEOLYSIS PROTEIN METABOLISM 1Department of Biological Sciences, University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA, 2Current address: Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA. Received 17 October 2011 Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential component of the immune system, Accepted because it trims peptide precursors and generates the N-termini of the final MHC class I-restricted epitopes. 23 November 2011 To examine ERAP1’s unique properties of length- and sequence-dependent processing of antigen precursors, we report a 2.3 A˚ resolution complex structure of the ERAP1 regulatory domain. Our study Published reveals a binding conformation of ERAP1 to the carboxyl terminus of a peptide, and thus provides direct 13 December 2011 evidence for the molecular ruler mechanism. Correspondence and ntigen processing is an integral part of cell-mediated immune surveillance and responses that involve 1 requests for materials MHC-restriction and T cell recognition . Processed antigenic peptides, when presented on cell surface by MHC molecules to T cells, serve as identity tags to be monitored and responded to by our immune should be addressed to A system. To be presented by MHC class I molecules, endogenous antigens need to be cut into 8 to 11 residues in H.-C.G. length in order to fit into the MHC binding groove2,3. The precursors of class I antigenic peptides are generated (HwaiChen_Guo@ mainly by proteasomes in the cytosol to have the correct C-terminus but with an N-terminal extension of several uml.edu) amino acids4.
    [Show full text]
  • Disease-Associated Polymorphisms in ERAP1 Do Not Alter Endoplasmic Reticulum Stress in Patients with Ankylosing Spondylitis
    Genes and Immunity (2015) 16, 35–42 © 2015 Macmillan Publishers Limited All rights reserved 1466-4879/15 www.nature.com/gene ORIGINAL ARTICLE Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis TJ Kenna1, MC Lau1, P Keith1, F Ciccia2, M-E Costello1, L Bradbury1, P-L Low1, N Agrawal1, G Triolo2, R Alessandro2, PC Robinson1, GP Thomas1 and MA Brown1 The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27+ but not HLA-B27− AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27+ERAP1risk, HLA-B27+ERAP1protective, HLA-B27−ERAP1risk and HLA- B27−ERAP1protective. Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27+ and HLA-B27− cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27.
    [Show full text]
  • Interferon-Gamma (IFN-Γ): Exploring Its Implications in Infectious Diseases
    BioMol Concepts 2018; 9: 64–79 Review Open Access Gunjan Kak*#, Mohsin Raza#, Brijendra K Tiwari Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases Journal xyz 2017; 1 (2): 122–135 https://doi.org/10.1515/bmc-2018-0007 of disease mechanisms and these aspects also manifest received February 13, 2018; accepted April 20, 2018.1 The First Decade (1964-1972) enormous therapeutic importance for the annulment of Abstract: A key player in driving cellular immunity, IFN-γ various infections and autoimmune conditions. Researchis capable Article of orchestrating numerous protective functions to heighten immune responses in infections and cancers. Keywords: Cytokine; IFN-γ; Immune Response; Infectious MaxIt Musterman, can exhibit its immunomodulatoryPaul Placeholder effects by enhancing Diseases; Mycobacteria; Host-pathogen interaction; antigen processing and presentation, increasing leukocyte Cytokine therapy. Whattrafficking, Is So inducing Different an anti-viral About state, boosting the anti- Neuroenhancement?microbial functions and affecting cellular proliferation and apoptosis. A complex interplay between immune IFN-γ: An Introduction Wascell ist activity so and anders IFN-γ through am coordinatedNeuroenhancement? integration of signals from other pathways involving cytokines The human immune system is evolved to eradicate or Pharmacologicaland Pattern Recognition and Mental Receptors Self-transformation (PRRs) such as in containEthic any pathogenic challenge and eliminate self- ComparisonInterleukin (IL)-4, TNF-α, Lipopolysaccharide (LPS), altered cancerous cells. In this regard, IFN-γ has a critical PharmakologischeType-I Interferons und(IFNs) mentale etc. leads Selbstveränderung to initiation of a imrole in recognizing and eliminating pathogens. IFN-γ, cascade of pro-inflammatory responses. Microarray data being the central effector of cell mediated immunity, can ethischen Vergleich has unraveled numerous genes whose transcriptional coordinate a plethora of anti-microbial functions.
    [Show full text]
  • ERAP1) Reveal the Molecular Basis for N-Terminal Peptide Trimming
    Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming Grazyna Kochana,1, Tobias Krojera,1, David Harveyb, Roman Fischerc, Liye Chend, Melanie Vollmara, Frank von Delfta, Kathryn L. Kavanagha, Matthew A. Brownb,e, Paul Bownessb,d, Paul Wordsworthb, Benedikt M. Kesslerc, and Udo Oppermanna,b,2 aStructural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, United Kingdom; bBotnar Research Center, National Institute for Health Research Oxford Biomedical Research Unit, Oxford OX3 7LD, United Kingdom; cHenry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom; dWeatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom; and eUniversity of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia Edited* by Marc Feldmann, Imperial College London, United Kingdom, and approved March 15, 2011 (received for review January 26, 2011) Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunc- However, based on biochemical studies a model of ERAP1 activ- tional enzyme involved in trimming of peptides to an optimal ity was suggested that involves the binding of a 9–15-mer peptide length for presentation by major histocompatibility complex to the active site of ERAP1, where successively N-terminal resi- (MHC) class I molecules. Polymorphisms in ERAP1 have been asso- dues are cleaved off until the N-terminal part of the peptide is no ciated with chronic inflammatory diseases, including ankylosing longer reaching the active site. The rate at which this process spondylitis (AS) and psoriasis, and subsequent in vitro enzyme occurs appears to be peptide sequence specific (13, 14).
    [Show full text]
  • An Allelic Variant in the Intergenic Region Between ERAP1 and ERAP2
    www.nature.com/scientificreports OPEN An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse Received: 5 February 2018 Accepted: 19 June 2018 expression of the two genes Published: xx xx xxxx Fabiana Paladini1, Maria Teresa Fiorillo1, Carolina Vitulano1, Valentina Tedeschi1, Matteo Piga2, Alberto Cauli2, Alessandro Mathieu2 & Rosa Sorrentino1 The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly infuences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a signifcant higher expression of ERAP1. We therefore show here for the frst time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specifc therapeutic approaches. Te ER-resident aminopeptidases ERAP1 and ERAP2 are ubiquitous, zinc-dependent multifunctional enzymes involved in immune activation and infammation1–3, blood pressure regulation4,5 and antigenic peptide repertoire shaping6–10].
    [Show full text]
  • ERAP1) Reveal the Molecular Basis for N-Terminal Peptide Trimming
    Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming Grazyna Kochana,1, Tobias Krojera,1, David Harveyb, Roman Fischerc, Liye Chend, Melanie Vollmara, Frank von Delfta, Kathryn L. Kavanagha, Matthew A. Brownb,e, Paul Bownessb,d, Paul Wordsworthb, Benedikt M. Kesslerc, and Udo Oppermanna,b,2 aStructural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, United Kingdom; bBotnar Research Center, National Institute for Health Research Oxford Biomedical Research Unit, Oxford OX3 7LD, United Kingdom; cHenry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom; dWeatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom; and eUniversity of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia Edited* by Marc Feldmann, Imperial College London, United Kingdom, and approved March 15, 2011 (received for review January 26, 2011) Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunc- However, based on biochemical studies a model of ERAP1 activ- tional enzyme involved in trimming of peptides to an optimal ity was suggested that involves the binding of a 9–15-mer peptide length for presentation by major histocompatibility complex to the active site of ERAP1, where successively N-terminal resi- (MHC) class I molecules. Polymorphisms in ERAP1 have been asso- dues are cleaved off until the N-terminal part of the peptide is no ciated with chronic inflammatory diseases, including ankylosing longer reaching the active site. The rate at which this process spondylitis (AS) and psoriasis, and subsequent in vitro enzyme occurs appears to be peptide sequence specific (13, 14).
    [Show full text]