Abstract
A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.
Highlights
A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet’s disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder
We addressed two issues concerning the relationship between antigen processing and presentation by HLA-B*51 and BD: 1) the effects of the BD-associated ERAP1 variant on the HLA-B*51 peptidome and 2) how this peptidome is affected by polymorphism between two BD-associated B*51 subtypes
It was heterozygous for ERAP2, only the Lys-392 allotype of ERAP2 is expressed due to linkage disequilibrium of the Asn-392 variant with a polymorphism that impairs the expression of the protein [26]
Summary
A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap, is associated with the autoinflammatory disorder Behçet’s disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. In the BDassociated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues These effects were readily explained by the low activity of Hap and the differential susceptibility of X–Pro and X–Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. To assess the effect of this ERAP1 context, as well as the effect of polymorphism between two BD-associated subtypes, on the HLA-B*51 peptidome, the B*51:08 ligands were compared with those of HLA-B*51:01 generated in a more active ERAP1 background and identified in our previous study [25]. The differences observed allowed us to establish the effects of ERAP1 on the HLA-B*51 peptidome and to distinguish them from those due to subtype polymorphism
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