Guasp, PabloBarnea, EilonGonzalez-Escribano, M FranciscaJimenez-Reinoso, AnaïsRegueiro, Jose RAdmon, ArieLopez-de-Castro, Jose A2023-01-252023-01-252017-06-09Guasp P, Barnea E, González-Escribano MF, Jiménez-Reinoso A, Regueiro JR, Admon A, et al. The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing. J Biol Chem. 2017 Jun 9;292(23):9680-9689.http://hdl.handle.net/10668/11136A 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/aminopeptidaseantigen presentationantigen processingmass spectrometry (MS)peptidesproteomicsAminopeptidasesBehcet SyndromeCell LineHLA-B51 AntigenHumansKiller Cells, NaturalMinor Histocompatibility AntigensPeptidesPolymorphism, GeneticProtein DomainsT-Lymphocytesresearch article28446606open accessAfectoPéptidosEnfermedadRetículo endoplásmicoAntígenos HLA-BProliferación celular10.1074/jbc.M117.7891801083-351XPMC5465491http://www.jbc.org/content/292/23/9680.full.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465491/pdf