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The Role of ER‐resident Lectin Chaperone UGT1 in MHC Class I Peptide Loading
Author(s) -
Arshad Najla,
Cresswell Peter
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.604.13
Subject(s) - calnexin , calreticulin , mhc class i , transporter associated with antigen processing , antigen processing , major histocompatibility complex , antigen presentation , chaperone (clinical) , microbiology and biotechnology , mhc restriction , glycan , chemistry , biology , antigen , biochemistry , glycoprotein , cytotoxic t cell , endoplasmic reticulum , immunology , medicine , pathology , in vitro
The phenomenon of antigen processing and presentation aids the immune system in distinguishing between normal and diseased cells. Antigen presentation by MHC class I heavy chain‐β2m heterodimers (MHC‐I) to CD8 + T cells requires association of MHC‐I with peptides, a process that occurs in in the ER. Binding is facilitated by the Peptide Loading Complex (PLC), which consists of the TAP transporter, the ‘peptide editor’ tapasin, which is disulfide linked to the thiol‐oxidoreductase ERp57, and a lectin chaperone, calreticulin (CRT). Heterodimers without peptides are inherently unstable and are not expressed on the cell surface. Even when MHC‐I associates with a peptide, only those molecules loaded with a peptide deemed “optimal” by quality control mechanisms in the ER proceed to the cell surface. Proteins involved in this quality control include the ER‐resident lectin chaperones calnexin and CRT that interact with MHC‐I via its conserved N‐linked glycan. Once the peptide‐associated MHC‐I leaves the PLC, it can be a substrate for the enzyme UDP‐glucose:glycoprotein glucosyltransferase 1 (UGT1), which selectively reglucosylates the N‐linked glycan of the MHC‐I heavy chain. The glucosylated MHC‐I can then re‐associate with CRT in the PLC, allowing for additional rounds of peptide binding. This process is reminiscent of the ubiquitous calnexin‐calreticulin cycle and has been adapted by the cell for optimal antigen presentation by MHC‐I. However, in this case, MHC‐I is a folded and functional molecule. This study aims to understand the mechanism by which UGT1 recognizes a peptide/MHC‐I complex. Biochemical assays using purified UGT1 and the human MHC‐I allele HLA‐A2 unexpectedly showed that there is no strong correlation between the affinity of the associated peptide and reglucosylation of the HLA‐A2 glycan. Recognition may be based on conformational changes in MHC‐I induced by the peptide. Consistent with this, published hydrogen/deuterium exchange studies show that such changes occur near the glycosylation site, and are independent of the affinity of the peptide for MHC‐I. Support or Funding Information Cancer Research Institute Irvington Fellowship and The National Institutes of Health:R01AI09720605