Allele-specific Alterations in the Peptidome Underlie the Joint Association of HLA-A*29:02 and Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) with Birdshot Chorioretinopathy.

Molecular & Cellular Proteomics : MCP
Alejandro Sanz-BravoJosé A López de Castro

Abstract

Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2. In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The paradoxical effects on peptide length suggest that unproductive binding to ERAP2 might protect some peptides from ERAP1 over-trimming. The influence on N-terminal residues can be explained by a direct effect of ERA...Continue Reading

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Citations

Jul 29, 2018·Bioscience Reports·Emma Reeves, Edward James
Sep 15, 2018·Human Molecular Genetics·Jonas J W KuiperTimothy R D J Radstake
Sep 19, 2019·Molecular & Cellular Proteomics : MCP·Elena LorenteJosé A López de Castro
Nov 15, 2018·Frontiers in Immunology·José A López de Castro
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Nov 1, 2019·Molecular & Cellular Proteomics : MCP·Elena LorenteJosé A López de Castro
Nov 3, 2021·Investigative Ophthalmology & Visual Science·Sahar GelfmanUNKNOWN Regeneron Genetics Center

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