Pitch session 2Functional interation of endoplasmic reticulum aminopeptidase ERAP2 and the peptidome of the main MHC-I-associated inflammatory disorders

Several inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: Among them birdshot chorioretinopathy (HLA-A*29:02) and ankylosing spondylitis (HLA-B*27) have the strongest association with about 100 and 90% of patients being A*29:02 and B*27 positive, respectively. Genome –wide associated studies (GWAS) showed the significance of the endoplasmatic reticulum aminopeptidasas ERAP1 and ERAP2 in this MHC-I associated inflammatory diseases. Although ERAP2 has been primarily described as an accessory and complementary enzyme to the homologous ERAP1, the aim of this work was to study whether it could play distinct and important roles in processing antigenic peptides. HLA-B*27 and B*29-bound peptides were isolated from cell lines that differ in the expression or abscence of ERAP2, by immunoaffinity chromatography and acid extraction. Over 2000-4000 ligands were identified from each cell line and their relative abundance was established by quantitative tandem mass spectrometry and MaxQuant-based analyses. The comparison of HLA-B*27 and A*29-bound peptidomes from cells expressing ERAP2 or not revealed that ERAP2 expression induces significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence with ERAP1, reflect largely separate roles in their processing of MHC-I ligands. The magnitude of the effects in different peptidomes of ERAP2 suggests that it could affect not only specific antigen presentation, but also the pro-inflammatory and autoimmune potential of MHC-I molecules.