Abstract
Recently, we revealed that TAPBPR is a peptide exchange catalyst that is important for optimal peptide selection by MHC class I molecules. Here, we asked whether any other co-factors associate with TAPBPR, which would explain its effect on peptide selection. We identify an interaction between TAPBPR and UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1), a folding sensor in the calnexin/calreticulin quality control cycle that is known to regenerate the Glc1Man9GlcNAc2 moiety on glycoproteins. Our results suggest the formation of a multimeric complex, dependent on a conserved cysteine at position 94 in TAPBPR, in which TAPBPR promotes the association of UGT1 with peptide-receptive MHC class I molecules. We reveal that the interaction between TAPBPR and UGT1 facilities the reglucosylation of the glycan on MHC class I molecules, promoting their recognition by calreticulin. Our results suggest that in addition to being a peptide editor, TAPBPR improves peptide optimisation by promoting peptide-receptive MHC class I molecules to associate with the peptide-loading complex.
Highlights
The presentation of antigenic peptides to the immune system by MHC class I molecules is crucial in generating protective responses against infection and cancer
UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) was isolated in the immunoprecipitates from ZZ-TAPBPR-expressing cells, but not in control HeLaM cells transfected with an empty vector (Table 1), suggesting that UGT1 could be a novel binding partner for TAPBPR
As human TAPBPR lacks an N-linked glycan and UGT1 monitors glycoprotein folding by recognising hydrophobic patches near a Man9GlcNAc2 moiety (Trombetta et al, 1989; Caramelo et al, 2003, Caramelo et al, 2004; Ritter et al, 2005), it is highly unlikely that UGT1 functions directly in the quality control of TAPBPR
Summary
The presentation of antigenic peptides to the immune system by MHC class I molecules is crucial in generating protective responses against infection and cancer. Central to this process is the loading and optimisation of peptides onto MHC class I molecules within the peptide-loading complex (PLC) in the endoplasmic reticulum (ER) by tapasin, an MHC class I-dedicated chaperone that has been the focus of intense investigation for the past two decades (Sadasivan et al, 1996; Ortmann et al, 1997; Williams et al, 2002).
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