Reconstitution of glycan-driven MHC-I recycling reveals calreticulin as mediator between TAPBPR and tapasin.
TL;DR
A glycan-dependent chaperone network is defined, finely tuned by a combination of low-micromolar interactions between the constituents, that ensures efficient MHC-I maturation and illustrates fundamental principles of ER protein quality control.
Abstract
Protein folding in the endoplasmic reticulum (ER) relies on N-linked glycosylation and glycan remodeling to guide quality control. Major histocompatibility complex class I (MHC-I) molecules, essential for adaptive immunity, undergo a specialized maturation pathway involving the peptide-loading complex (PLC), the editor TAPBPR, the UDP-glucose:glycoprotein glucosyltransferase, and the lectin chaperone calreticulin. However, how glycan-dependent mechanisms coordinate MHC-I transfer between these factors has remained unclear. Using a fully reconstituted system, we show that retrograde transfer of peptide-receptive MHC-I from TAPBPR to tapasin requires calreticulin recognition of monoglucosylated MHC-I glycans. While calreticulin's C-terminal acidic helix is dispensable for releasing reglucosylated MHC-I from TAPBPR, it is essential for productive docking of MHC-I onto tapasin. These findings reveal a glycan-surveillance mechanism that enables retrieval of suboptimally loaded MHC-I molecules missed by the initial quality control at the PLC. Our work defines a glycan-dependent chaperone network, finely tuned by a combination of low-micromolar interactions between the constituents, that ensures efficient MHC-I maturation and illustrates fundamental principles of ER protein quality control.
