Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation

Abstract

Purpose of review: To 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 findings: ERAP1 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.

Summary: More 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 Behçet's disease and psoriasis, respectively.

Figure 1. Schematic diagram of ERAP1

The locations of common (>5% frequency) naturally occurring amino acid variants and their corresponding SNPs are shown. The rheumatic disease-associated variants (127, 349, 528, 575, 725, and 730) are shown in Figure 2.

Figure 2. Rheumatic disease-associated missense variants of ERAP1

A surface map of ERAP1 demonstrates the locations of six rheumatic disease-associated amino acid substitutions of ERAP1 (shown as red spheres). The surface coloring indicates the domain structures (I = blue, II = green, III = orange, IV = purple) and identifies the enzyme’s catalytic site (pink), which contains the catalytic Zn²⁺ molecule (black sphere). This model was created using 3MDJ and PyMol software. (Courtesy of M. Ombrello)