title: ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases.
abstract: The endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in the final processing of Major Histocompatibility Complex class I (MHC-I) ligands and with a significant influence in the stability and immunological properties of MHC-I proteins. ERAP1 polymorphism is associated with ankylosing spondylitis among HLA-B27-positive individuals and the altered enzymatic activity of natural variants has significant effects on the HLA-B27 peptidome, suggesting a critical pathogenetic role of peptides in this disease. Likewise, the association of ERAP1 with other MHC-I associated disorders and its epistasis with their susceptibility MHC alleles point out to a general role of the MHC-I peptidome in these diseases. The functional interaction between ERAP1 and HLA-B27 or other MHC-I molecules may be related to the processing of specific epitopes, or to a more general peptide-dependent influence on other biological features of the MHC-I proteins. In addition, from a consideration of the reported functions of ERAP1, including its involvement in angiogenesis and macrophage activation, a more complex and multi-level influence in the inflammatory and immune pathways operating in these diseases cannot be ruled out.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alvarez-Navarro
authors.forename: José A
authors.initials: JA
authors.lastname: López de Castro
mesh_terms: D000483:Alleles; D000626:Aminopeptidases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D015778:Minor Histocompatibility Antigens; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
chemical_list: D015796:HLA-B27 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human
keywords: Aminopeptidases; Ankylosing spondylitis; Antigen processing; ERAP1; HLA-B27; Spondyloarthropathies