Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme

Evnouchidou, Irini; Kamal, Ram P.; Seregin, Sergey S.; Goto, Yoshikuni; Tsujimoto, Masafumi; Hattori, Akira; Voulgari, Paraskevi V.; Drosos, Alexandros A.; Amalfitano, Andrea; York, Ian A.; Stratikos, Efstratios

doi:10.4049/jimmunol.1003337

Cited by 131 publications

(185 citation statements)

References 19 publications

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“…This observation is in accordance with a previous study showing that charged N-terminal residues were relatively protected from ERAP1 degradation (35). In vitro studies using synthetic peptides have shown that ERAP1 polymorphisms have substrate-dependent effects on enzyme activity (7,(36)(37)(38). A recent cell-based study showed that protective ERAP1 polymorphisms resulted in increased length and altered P1 residues of peptides bound to HLA-B*27:04 (39).…”

Section: Discussionsupporting

confidence: 92%

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Chen

Fischer

Peng

et al. 2014

Arthritis & Rheumatology

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Objective. HLA-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are the two strongest genetic factors predisposing to ankylosing spondylitis (AS). A key aminopeptidase in class I major histocompatibility complex presentation, ERAP1 potentially contributes to the pathogenesis of AS by altering HLA-B27 peptide presentation. The aim of this study was to analyze the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes (CTLs).Methods. ERAP1-silenced and -competent HeLa.B27 and C1R.B27 cells were isotope-labeled, mixed, lysed, and then immunoprecipitated using W6/32 or ME1 antibodies. Peptides bound to HLA-B27 were eluted and analyzed by tandem mass spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/ mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTLs was also studied.Results. In both HeLa.B27 and C1R.B27 cells, the proportion of 9-mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentages of longer peptides (11-13 mer) were increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than were N-terminally extended peptides lacking an arginine at position 2. In both HeLa.B27 cells and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced peptide recognition by HLA-B27-restricted KK10-specific CTLs following infection with recombinant vaccinia virus or transfection with minigenes expressing KK10 precursors. Presence of an AS-protective variant of ERAP1, K528R, as compared to wild-type ERAP1, reduced the peptide recognition by KK10 CTLs following transfection with extended KK10 minigenes.Conclusion. These results show that ERAP1 directly alters peptide binding and presentation by HLA-B27, thus demonstrating a potential pathogenic mechanism in AS. Inhibition of ERAP1 could potentially be used for treatment of AS and other ERAP1-associated diseases.The human leukocyte antigen HLA-B27 is very strongly associated with development of the common inflammatory rheumatic disease ankylosing spondylitis (AS). However, the pathogenic mechanism remains unclear. Recent genome-wide association studies have identified additional AS-associated genes, of which the strongest association is with endoplasmic reticulum aminopeptidase 1 (ERAP1) (1). The strong genetic association of AS with ERAP1 single-nucleotide polymorphisms has been confirmed in different populations (2-7).

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Section: Discussionsupporting

confidence: 92%

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Chen

Fischer

Peng

et al. 2014

Arthritis & Rheumatology

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“…This could make the two molecules differently prone to exchange peptides in the TGN where they can encounter a set of tissue-specific peptides different from those generated by the classical proteasomal machinery. Ultimately, the rate of peptide exchange will be influenced by the repertoire of peptides generated in the ER, which in turn depends on the trimming activity of ERAP1 that changes according to the allelic variants, some of which are strongly associated with AS (17,43).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules

Magnacca

Persiconi

Nurzia

et al. 2012

Journal of Biological Chemistry

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Nascent HLA-class I molecules are stabilized by proteasome-derived peptides in the ER and the new complexes proceed to the cell surface through the post-ER vesicles. It has been shown, however, that less stable complexes can exchange peptides in the Trans Golgi Network (TGN). HLA-B27 are the most studied HLA-class I molecules due to their association with Ankylosing Spondylitis (AS). Chimeric proteins driven by TAT of HIV have been exploited by us to deliver viral epitopes, whose cross-presentation by the HLA-B27 molecules was proteasome and TAP-independent and not restricted to Antigen-Presenting Cells (APC). Here, using these chimeric proteins as epitope suppliers, we compared with each other and with the HLA-A2 molecules, the two HLA-B*2705 and B*2709 alleles differing at residue 116 (D116H) and differentially associated with AS. We found that the antigen presentation by the two HLA-B27 molecules was proteasome-, TAP-, and APC-independent whereas the presentation by the HLA-A2 molecules required proteasome, TAP and professional APC. Assuming that such difference could be due to the unpaired, highly reactive Cys-67 distinguishing the HLA-B27 molecules, C67S mutants in HLA-B*2705 and B*2709 and V67C mutant in HLA-A*0201 were also analyzed. The results showed that this mutation did not influence the HLA-A2-restricted antigen presentation while it drastically affected the HLA-B27-restricted presentation with, however, remarkable differences between B*2705 and B*2709. The data, together with the occurrence on the cell surface of unfolded molecules in the case of C67S-B*2705 mutant but not in that of C67SB*2709 mutant, indicates that Cys-67 has a more critical role in stabilizing the B*2705 rather than the B*2709 complexes

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“…The most common protein variants, reported as ERAP1 allotypes, are encoded by haplotypes created by missense variant combinations of SNPs harboured in an ancestral haplotype found in humans as well as in primates [78]. The most investigated ERAP1 allotypes (from 10 to 13) [78,79] are distinguished by enzymatic functions with both qualitative (substrate preferences) and quantitative (high, intermediate and low activity variants) effects [5,64,[80][81][82]. Interestingly, some non-synonymous SNPs influence the gene expression level of ERAP1 [83].…”

Section: Hla-b27 a Molecule With Two Faces: Protection From Viral Inmentioning

confidence: 99%

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

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Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme

Cited by 131 publications

References 19 publications

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Characterization of a Proteasome and TAP-independent Presentation of Intracellular Epitopes by HLA-B27 Molecules

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

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