Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation

• Published in: Current opinion in rheumatology Vol. 27; no. 4; pp. 357 - 363
• Main Authors: Tran, Tri M, Colbert, Robert A
• Format: Journal Article
• Language: English
• Published: United States Copyright Wolters Kluwer Health, Inc. All rights reserved 01-07-2015
• Subjects: Aminopeptidases - genetics; Aminopeptidases - physiology; Genetic Predisposition to Disease; Haplotypes; Histocompatibility Antigens Class I - metabolism; HLA-B27 Antigen - immunology; Humans; Minor Histocompatibility Antigens; Polymorphism, Single Nucleotide; Rheumatic Diseases - genetics; Rheumatic Diseases - immunology
• ISSN: 1040-8711; 1531-6963
• DOI: 10.1097/BOR.0000000000000188

PURPOSE OF REVIEWTo review the recent developments in our understanding of endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) function in relation to its role in major histocompatibility complex (MHC) class I peptide presentation and human leukocyte antigen (HLA) class I-associated diseases.
RECENT FINDINGSERAP1 polymorphisms exhibiting loss-of-function have been associated with protection from AS. The aminopeptidase function of ERAP1 optimizes peptides for binding and presentation by MHC class I. Most of the studies have revealed reduced MHC class I expression in situations of reduced ERAP1 function. Under these circumstances, the presented peptides are often N-terminally extended, and cell surface complexes are unstable and fall apart more readily. In contrast, peptides presented by HLA-B*27 : 05 when ERAP1 is silenced are frequently extended on the C-terminus. Recent work has emphasized on the importance of assessing the function of allotypes encoded by ERAP1 haplotypes, rather than effects of single amino acid substitutions. The allotypes found in a series of AS patients were poorer at restoring HLA-B27 expression than allotypes found in unaffected controls, which may seem contrary to the genetic data linking loss-of-function to protection.
SUMMARYMore work is needed to understand how ERAP1 variants associated with risk and protection influence the quality and quantity of peptides available for binding to HLA class I molecules in the ER. Moreover, we need to determine allele-specific effects of ERAP1 variants in the context of HLA-B*51 and HLA-Cw*6, which are associated with Behçetʼs disease and psoriasis, respectively.