Protein folding in the endoplasmic reticulum (ER) is crucial for about one third of the mammalian proteome. N-linked glycosylation and subsequent restructuring of glycans barcodes glycoproteins during their maturation. UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) and the chaperones calnexin and calreticulin together with glucosidase I play a vital role in this process. MHC I molecules, key for adaptive immunity, additionally rely on the specialized chaperones tapasin and TAPBPR (TAP-binding protein-related) for their maturation and loading of antigenic peptides. Here, we delineate the functional interplay between tapasin, TAPBPR, UGGT1, and calreticulin, during recycling of MHC I molecules via purified components. The transfer of peptide-receptive MHC I from TAPBPR back to tapasin relies on the recognition of the mono-glucosylated glycan by calreticulin. Our findings unveil a finetuned dynamic network of glycan-dependent and MHC I-specific chaperones that guarantee maturation of MHC I molecules and highlight the fundamental processes driving ER protein quality control.

Supporting information and Raw Data contributing to the paper 'Mechanism of the glycan-driven MHC I quality control cycle mediated by a dedicated chaperone network'.