How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins

Abstract

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

An Overview on ERAP Roles in Infectious Diseases

“…Ten years later, using engineered ERAP1-ERAP2 complexes, I. Evnouchidou and colleagues verified that heterodimer formation changes enzymatic features and increases peptide-trimming efficiency, thus allowing the generation of a wider and more immunogenic antigenic repertoire [8]. Indeed, the complementary activity of the two aminopeptidases leads to the generation of a variegated antigenic repertoire, which may be altered in individuals lacking either protein [12]. Overall, it has been demonstrated that the structural changes made by ERAP1 and ERAP2 represent a key step in mature antigenic epitope generation [12].…”

“…Indeed, the complementary activity of the two aminopeptidases leads to the generation of a variegated antigenic repertoire, which may be altered in individuals lacking either protein [12]. Overall, it has been demonstrated that the structural changes made by ERAP1 and ERAP2 represent a key step in mature antigenic epitope generation [12].…”

“…These two genes are highly polymorphic, although ERAP2 gene exhibits not as many single nucleotide polymorphisms (SNPs) as ERAP1. Since these aminopeptidases are involved in the antigen processing pathway, a series of genetic studies have linked their genetic variants to modifications in their functioning that could easily lead to MHC-I-associated disorder onset [12,22,23], including infectious diseases ( Table 1 and Figure 1).…”

“…Moreover, they differ from each other by alternative splicing at a secondary splice site at exon 15 and they are both translated into proteins lacking the catalytic domain [33]. Previous studies had already demonstrated that full-length ERAP2 tends to form hetero-and homodimers with ERAP1, in order to perform its trimming activity in a more efficient way [12]. Therefore, the author speculates that the expression of the two short flu-specific isoforms may exert a dominant negative effect on wild type (WT) ERAP1 or ERAP2.…”

“…Therefore, the author speculates that the expression of the two short flu-specific isoforms may exert a dominant negative effect on wild type (WT) ERAP1 or ERAP2. This would lead to an altered peptide processing, possibly conferring an advantage against infection by presenting a more immunogenic antigen repertoire [12] (Figure 2). Both haplotypes-and relative transcripts-may therefore provide fitness advantage in diverse environmental conditions, providing a plausible explanation to HAPB maintenance at intermediate frequencies by balancing selection [12].…”