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Influence of ERAP1 and ERAP2 Gene Polymorphisms on Disease

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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. During the process of MHC class I antigen presentation, they play a role to ensure the correct assembly of the peptide-loading An important part of the human immune system is the presentation complex (PLC) [5,6]. of endogenous peptides by major histocompatibility complex (MHC) ERAPs, including ERAP1 and ERAP2, were initially identified as class I molecules to CD8+ T cells. This educates the immune system to homologues of human placental leucine aminopeptidase or insulin- differentiate between self-derived and foreign antigens, resulting inthe regulated aminopeptidase, and they belong to the oxytocinase sub- clearance of infected or tumor cells. This presentation process is the family of the M1 zinc metallopeptidases family [7]. They are expressed result of a series of reactions: 1) antigens are degraded in the cytosol in various human tissues, such as the heart, placenta, and spleen, and into peptide precursors by the proteasome; 2) these precursors trans- are regulated by interferon-γ (IFN-γ) [3,8]. ERAP1 and ERAP2 share locate, via transporter associated with antigen presentation (TAP) approximately 50% amino acid identity to common zinc-binding motifs proteins, into the endoplasmic reticulum (ER) lumen; 3) within the ER, for the enzymatic activity [9,10]. These enzymes trim the N-terminal of the precursors are trimmed by endoplasmic reticulum aminopeptidases MHC I-bound precursor peptides into the correct and final lengths of (ERAPs) into final peptides and loaded onto MHC class I molecules; and 8–10 amino acids, which stabilizes the conformation of the MHC class I 4) peptide-MHC class I complexes are released from the ER and trans- PLC. This is an essential step in exporting the MHC class I with bound ported via the Golgi to the plasma membrane for antigen presentation peptide to the cell surface [6,9,11,12]. Abbreviations: AAU, Acute anterior uveitis; AFR, African; AMR, Admixed American; AS, ankylosing spondylitis; BD, Behcet's disease; BSCR, Birdshot chorior- etinopathy; BU, Birdshot Uveitis; CC, Cervical carcinoma; CD, Crohn's disease; CT, Congenital Toxoplasmosis; EAS, East Asian; ER, endoplasmic reticulum; ERA, enthesitis-related arthriti; ERAPs, endoplasmic reticulum aminopeptidases; EUR, European; GWAS, genome-wide association study; HCV, Hepatitis C virus chronic infection; HLA, human leucocyte antigen; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; JIA, Juvenile Idiopathic Arthritis; KD, Kawasaki disease; LMP, molecular weight peptide; MHC, major histocompatibility complex; MS, multiple sclerosis; NSCLC, non-small cell lung carcinoma; PE, Preeclampsia; PLC, peptide-loading complex; PS, psoriasis; PsA, psoriatic arthritis; PsC, psoriatic without arthritis; PV, psoriasis vulgaris; RA, rheumatoid arthritis; SAS, South Asian; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphisms; SpA, spondyloarthritis; T1D, Type 1 Diabetes; TAP, transporter associated with antigen presentation ⁎ Corresponding author at: Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China. E-mail address: [email protected] (L. Shi). https://doi.org/10.1016/j.humimm.2019.02.011 Received 7 December 2018; Received in revised form 14 February 2019; Accepted 21 February 2019 Available online 21 February 2019 0198-8859/ © 2019 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. Y. Yao, et al. Human Immunology 80 (2019) 325–334 1.2. The gene construction and molecular structure of ERAPs activity and selectivity of these proteins [17,20,22–25]. Furthermore, these SNPs are located at essential structural positions that may change The human ERAP genes are located on chromosome 5q15 in op- the conformation of ERAP1 and ERAP2 [9,14,24]. posite orientation. The ERAP1 gene is 47,379 bp in length and com- Population studies, disease association studies, and evolutionary prises 20 exons. Exon 6 and 7 encode the GAMEN consensus sequence analyses have suggested that the high level of polymorphisms in the and zinc-binding motif, respectively. Exon 19 encodes the splicing human immune system is a result of host-pathogen balance selection donor sequences. ERAP1 has two isoforms, isoform 1 and isoform 2. and evolutionary pressures. Since ERAPs is involved in the antigen Isoform 1 contains 948 amino acids, and isoform 2 contains 941 amino presentation process, it may be a target for the natural selection by acids with its termination codon in exon 19. The ERAP2 gene is several pathogens [26–28]. Sequence alignment analyses have revealed 41,438 bp in length and comprises of 19 exons, in which consensus that both ERAP1 and ERAP2 genes have evolved under purifying se- motifs are encoded by exon 6 and 7. In exon 10, an alternative splice lection. This balance selection has driven the recurrent appearance of may cause an insertion of a stop codon, producing a non-catalytic, destabilizing variants in ERAP2, and using 3-D-structure protein ana- truncated form of ERAP2 [9,13]. lysis, three positively selected sites 416Y, 420V, and 857A have been The crystal structure of ERAP1 revealed typical HEXXH(X18)E zinc- identified, but appear to not be involved in the proteolytic activityof binding and GAMEN motifs, consisting of four domains-Domain I (re- the protein [29]. Furthermore, one of the positively selected sites sidues 46–254), Domain II (residues 255–529), Domain III (residues (R528K, rs30187) in ERAP1 has been identified as a target of balancing 530–614), and Domain IV (residues 615–940) [11,14]. Domain I con- selection [26,29] sists of eight stranded β-sheets and docks on top of domain II. Domain II Although ERAP1 and ERAP2 share 51% sequence homology and can contains the active site with the GAMEN and zinc-binding/gluzincin form heterodimers, the evolution of these two genes is different [4]. motifs. Among the conserved catalytic residues of M1 aminopeptidases, Unlike ERAP1, which widely exists in mammals, ERAP2 does not exist Glu320, His353, Glu354, His357, and Glu376, but not Tyr438, are in rodents, including mice, rats, and guinea pigs. Evolutionary studies structurally accommodated at an essentially identical position in Do- suggest that ERAP2 originated from a relatively recent duplication of main II. Domain III is similar to domain I, while domain IV is composed the ERAP1 gene [28]. Frequency distribution analyses in different po- solely of α-helices [9]. pulations found that ERAP2 showed a strong and consistent signature The ERAP1 molecule can crystalize in two conformations, either a under balancing selection, maintaining intermediate-frequency alleles. closed conformation or an open conformation. The closed conformation The estimated coalescent time of ERAP2 is about 1.44 Mya, while the produces an active catalytic pocket within a large cavity formed by the common ancestor of ERAP1 variants is about 2.84 Mya [28]. domains I, II, and IV, while the open conformation is rather catalyti- cally inactive due to a lack of an active catalytic pocket. Two major 2. ERAP1 and ERAP2 gene polymorphisms in populations differences between the closed and open conformations may critically affect ERAP1 activity. The extensive domain transition between both 2.1. Polymorphisms of the ERAP1 gene in different populations conformations is essential for the bind-cleave-release catalytic activity of the enzyme during the peptide trimming process [11,15]. Recent Since the genetic diversity of different ethnicities may contaminate study found some key ERAP1 variants may lead to allele-dependent the disease association results, we collected all the SNPs that were re- alternate expression of two distinct isoforms and significant differ- ported to be associated
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