title: Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome.
abstract: Ankylosing spondylitis (AS) is an inflammatory disease strongly associated with the Major Histocompatibility Complex class I (MHC-I) allotype HLA-B*27. The endoplasmic reticulum aminopeptidases (ERAP)1 and 2, which trim peptides to their optimal length for MHC-I binding, are also susceptibility factors for this disease. Both highly active ERAP1 variants and ERAP2 expression favor AS, whereas loss-of-function ERAP1 and loss-of-expression ERAP2 variants are protective. Yet, only ERAP1 is in epistasis with HLA-B*27. We addressed two issues concerning the functional interaction of ERAP1 and ERAP2 with the HLA-B*27 peptidome in human cells: 1) distinguishing the effects of ERAP1 from those of ERAP2, and 2) determining the influence of ERAP2 in distinct ERAP1 contexts. Quantitative comparisons of the HLA-B*27:05 peptidomes from cells with various ERAP1/ERAP2 phenotypes were carried out. When cells expressing ERAP2 and either high or low activity ERAP1 variants were compared, increased amounts of nonamers, relative to longer ligands, and decreased amounts of peptides with Ala1, were observed in the more active ERAP1 context. When cells expressing ERAP2 in a low activity ERAP1 context or lacking ERAP2 but expressing a highly active ERAP1 variant were compared, the same effects on peptide length and Ala1, but also significantly lower amounts of peptides with N-terminal basic residues and lower affinity of the peptidome, were observed in the ERAP2-positive context. Thus, ERAP1 and ERAP2 have significant and distinct effects on the HLA-B*27 peptidome, suggesting that both enzymes largely act as separate entities in vivo. This may explain their different patterns of association with AS.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma), Madrid, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Martín-Esteban
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma), Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sanz-Bravo
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma), Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Guasp
authors.affiliation: Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.affiliation: Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma), Madrid, Spain. Electronic address: aldecastro@cbm.csic.es.
authors.forename: José A
authors.initials: JA
authors.lastname: López de Castro
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008024:Ligands; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000276:immunology; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000939:Epitopes; D015796:HLA-B27 Antigen; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human
keywords: Ankylosing spondylitis; ERAP1; ERAP2; HLA-B*27