The Behçet’s Disease associated Hap10 variant of ERAP1 generates a low affinity HLA-B*51 peptidome through differential processing of two subpeptidomes

ABSTRACT: HLA-B*51, the main risk factor for Behçet’s disease (BD), binds two main subpeptidomes consisting of low affinity peptides with Ala as their second amino acid and higher affinity peptides with Pro at this position. A low activity variant of ERAP1, Hap10, is uniquely associated with BD susceptibility in epistasis with HLA-B*51. The peptidome presented by HLA-B*51:08 in a cell line expressing Hap10 was compared with the HLA-B*51:01 peptidome from a cell line expressing higher activity variants of ERAP1. The differences due to ERAP1 could be clearly distinguished from those due to subtype polymorphism. The latter should not affect disease susceptibility, since both HLA-B*51 subtypes are associated with BD. In the lower activity, BD-associated, ERAP1 context longer peptides were generated, the Pro2 subpeptidome was significantly reduced, and the Ala2 subpeptidome was correspondingly increased and showed a higher frequency of ERAP1-susceptible P1 residues. These effects are readily explained by the low activity of the disease-associated Hap10 variant, and together resulted in a significantly altered HLA-B*51 peptidome of lower affinity. The differences between both B*51 subtypes affected residue usage at various internal positions of the peptide ligands, including P3, where B*51:01 showed preference for aromatic residues whereas B*51:08 preferred smaller and polar ones. The profound effects of the BD-associated Hap10 haplotype on the nature and affinity of HLA-B*51/peptide complexes could significantly alter T-cell and NK cell recognition, providing a basis for the joint association of ERAP1 and HLA-B*51 to BD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Disease

SUBMITTER: Eilon Barnea  

LAB HEAD: Arie Admon

PROVIDER: PXD006215 | Pride | 2018-10-24

REPOSITORIES: Pride