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Genetic Associations and Functional Characterization of M1 Aminopeptidases and Immune-Mediated Diseases

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Genetic Associations and Functional Characterization of M1 Aminopeptidases and Immune-Mediated Diseases Genes and Immunity (2014) 15, 521–527 © 2014 Macmillan Publishers Limited All rights reserved 1466-4879/14 www.nature.com/gene REVIEW Genetic associations and functional characterization of M1 aminopeptidases and immune-mediated diseases N Agrawal and MA Brown Endosplasmic reticulum aminopeptidase 1 (ERAP1), endoplasmic reticulum aminopeptidase 2 (ERAP2) and puromycin-sensitive aminopeptidase (NPEPPS) are key zinc metallopeptidases that belong to the oxytocinase subfamily of M1 aminopeptidase family. NPEPPS catalyzes the processing of proteosome-derived peptide repertoire followed by trimming of antigenic peptides by ERAP1 and ERAP2 for presentation on major histocompatibility complex (MHC) Class I molecules. A series of genome-wide association studies have demonstrated associations of these aminopeptidases with a range of immune-mediated diseases such as ankylosing spondylitis, psoriasis, Behçet’s disease, inflammatory bowel disease and type I diabetes, and significantly, genetic interaction between some aminopeptidases and HLA Class I loci with which these diseases are strongly associated. In this review, we highlight the current state of understanding of the genetic associations of this class of genes, their functional role in disease, and potential as therapeutic targets. Genes and Immunity (2014) 15, 521–527; doi:10.1038/gene.2014.46; published online 21 August 2014 INTRODUCTION and apoptosis. Aminopeptidases hydrolyze a polypeptide’s It has long been established that the ‘seronegative’ diseases terminal amino-acid peptide bond, leading to the degradation ankylosing spondylitis (AS), psoriasis, Behçet’s disease and of their target substrate and release of amino acids which can be inflammatory bowel disease (IBD) share a tendency to co- recycled to form other proteins in the body. segregate in families, as well as various clinical and genetic In mammals, the M1 aminopeptidase family consists of five features, such as (with the exception of IBD) association with HLA integral transmembrane proteins: aminopeptidase A, thyrotropin- Class I loci, and association with axial spondyloarthritis. Genome- releasing hormone-degrading ectoenzyme, aminopeptidase N, wide association studies are identifying increasing evidence of ERAP1 and Leucyl/Cystinyl Aminopeptidase (LNPEP); and four non- broader genetic similarity between these diseases, notably with transmembrane enzymes: aminopeptidase B, NPEPPS, Leukotri- shared associations in the IL23R pathway, and more recently in ence A4 and ERAP2.6 This review focuses on the aminopeptidases associations with genes encoding M1 aminopeptidases, such as ERAP1, ERAP2 and NPEPPS that have been genetically associated endoplasmic reticulum aminopeptidase 1 (ERAP1), endoplasmic with human disease. reticulum aminopeptidase 2 (ERAP2) and NPEPPS (puromycin- ERAP1 is a type II integral membrane enzyme, whereas sensitive aminopeptidase). This review discusses the genetics of ERAP2 and NPEPPS are non-transmembrane enzymes. ERAP1 this class of genes and their association with immune-mediated and ERAP2 share ~ 49% sequence homology, LNPEP and ERAP1 diseases (IMDs), their functional role in disease and promise as ~ 44%, whereas NPEPPS shares ~ 40% sequence homology to therapeutic targets. the three aminopeptidases. The protein sequence alignment (Supplementary Figure S1) reveals the presence of a GAMEN and HELAH motifs that are conserved in six aminopeptidases except M1 AMINOPEPTIDASE FAMILY thyrotropin-releasing hormone-degrading ectoenzyme, amino- The M1 aminopeptidase family is ubiquitously expressed in tissue peptidase B, leukotrience A4 and excluding aminopeptidase A types, and within cells is found mostly in cytoplasm, endoplasmic (non-conserved HELAH motif). The rooted-phylogenetic tree reticulum (ER) and as membrane components. M1 aminopepti- (Supplementary Figure S2) of the nine aminopeptidases reveals dases belong to MA clan1,2 that are primarily zinc-dependent close genetic homology between ERAP1, ERAP2 and LNPEP enzymes in which two of the zinc ligands are the histidines in the whereas NPEPPS is far distant from the three proteins. Similarly, highly conserved motif: His-Glu-Xaa-Xaa-His (‘HEXXH’) and gluta- APB and LTA4H are structurally and genetically but not mate are a catalytic residue. They also have highly conserved functionally related.7 The mouse homolog of ERAP1 has 85% GAMEN motifs essential for enzyme activities. Tertiary structures sequence homology with human ERAP1. ERAP2 is absent in have been solved for several M1 aminopeptidases,3–5 and all have rodents and the mouse homolog of NPEPPS has 93% sequence the catalytic active site located between the domains I and II. homology to its human counterpart. M1 aminopeptidases are also known to be critically involved in the ERAP1 and ERAP2 in particular are known to trim peptides that regulation of many cellular processes such as cell cycling, growth are destined for major histocompatibility complex (MHC) class I University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. Correspondence: Professor MA Brown, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. E-mail: [email protected] Received 2 June 2014; accepted 3 June 2014; published online 21 August 2014 Enzyme-based targeted therapies for IMDs N Agrawal and MA Brown 522 Table 1A. Immune-mediated disease associated ERAP1, ERAP2 and NPEPPS polymorphism Gene SNP Chr. Pos. Risk allele MAF Coding change Functional activity rel. to wt protein Disease ERAP1 rs30187 96124330 T 0.33 K528R Reduced activity AS, Psoriasis ERAP1 rs17482078 96118866 C 0.22 R725Q Reduced activity AS T Q725R No change Behçet’s disease ERAP1 rs27524 96101944 A 0.36 —— Psoriasis ERAP1 rs10050860 96122210 C 0.77 D575N No change AS ERAP1 rs27044 96118852 C 0.65 Q730E Reduced activity AS ERAP2 rs2549782 96231000 T 0.5 N392K Reduced activity AS, Psoriasis ERAP2 rs2248374 96235896 A 0.45 — Loss of mRNA and absence of ERAP2 protein AS, IBD ERAP2 rs2549794 96244549 C 0.35 —— IBD ERAP2 rs2910686 96252589 T 0.42 —— AS NPEPPS rs9901869 45575206 G 0.49 —— AS Abbreviations: ERAP1, endoplasmic reticulum aminopeptidase 1; ERAP2, endoplasmic reticulum aminopeptidase 2; NPEPPS, Puromycin-sensitive aminopeptidase; SNP, single-nucleotide polymorphism; MAF, minor allele frequency; AS, Ankylosing Spondylitis; IBD, inflammatory bowel disease. Non- synonymous (ns) and synonymous (s) changes in the strands of ERAP1, ERAP2 and NPEPPS are shown. Chromosome position and Amino acid (AA) residue numbering are from Human ERAP1 Isoform 2 (Accession No. Q9NZ08-2), Human ERAP2 Isoform 1 (Accession No. Q6P179-1), Human NPEPPS Isoform 1 (Accession No. P56537-1). Table 1B. Linkage disequilibrium (r2) between marker pairs across ERAP1/ERAP2 genotyped in Wellcome Trust Case Control 2 controls9 rs27524 rs17482078 rs10050860 rs30187 rs2549782 rs27524 96101944 1.00 0.01 0.14 0.95 0.13 rs17482078 96118866 0.01 1.00 0.07 0.01 0.05 rs10050860 96122210 0.14 0.07 1.00 0.15 0.79 rs30187 96124330 0.95 0.01 0.15 1.00 0.12 rs2549782 96231000 0.13 0.05 0.79 0.12 1.00 Abbreviations: ERAP1, endoplasmic reticulum aminopeptidase 1; ERAP2, endoplasmic reticulum aminopeptidase 2. antigen presentation. Although there are reported associations of Since the discovery of the association of ERAP1 variants with AS, the genes encoding these enzymes with pre-eclampsia,8,9 cervical genome-wide significant association of ERAP1 variants rs27524 cancer10,11 and type 1 diabetes,12 these findings have not (carried on the same haplotype as rs30187) have also been achieved genome-wide significance and have not all replicated reported with psoriasis31 and rs30187 with Behçet’s disease.17,18 in other larger data sets, and are therefore of uncertain status. Whether or not the rs10050860-rs17482078 haplotype is also Genetic association of ERAP1 and ERAP2 is, however, definite with associated with these diseases has not been reported. While the several ‘seronegative’ IMDs including AS,13–15 psoriasis,16 Behçet’s ERAP1 association with psoriasis is concordant (same haplotype disease,17,18 and IBD19–21 (discussed further below). It is remark- with the same direction of association), in Behçet’s disease the able to note that their genetic analyses have revealed that the association is discordant, with the minor allele being a risk factor natural polymorphisms involving altered DNA sequence and for Behçet’s disease, whereas it is protective for AS and psoriasis. reduced protein function in these genes result in protection from Given the strong association of AS with the HLA Class I allele IMDs, raising the possibility that their inhibition could represent a HLA-B27 and the functional role of ERAP1 in trimming peptides novel class of therapeutic drug treatment for these diseases. before HLA Class I incorporation, Evans et al. tested whether ERAP1 variants show evidence of gene–gene interaction with HLA-B27.23 This was demonstrated in three separate case–control GENETIC ASSOCIATIONS OF M1 AMINOPEPTIDASES WITH cohorts, making this the first replicated example of gene–gene DISEASE interaction in any common human disease. Association with The first reported genome-wide significant association of any ERAP1 was only observed in HLA-B27-positive cases. This finding aminopeptidase with disease was with single-nucleotide poly- has recently been extended with the demonstration that the morphisms (SNPs)
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