Regulated N-glycosylation controls chaperone function and receptor trafficking
Mengxiao Ma, Ramin Dubey, Annie Jen, Ganesh V. Pusapati, Bharti Singal, Evgenia Shishkova, Katherine A. Overmyer, Valérie Cormier‐Daire, Juliette Fédry, L. Aravind, Joshua J. Coon, Rajat Rohatgi
Abstract
One-fifth of human proteins are N-glycosylated in the endoplasmic reticulum (ER) by two oligosaccharyltransferases, OST-A and OST-B. Contrary to the prevailing view of N-glycosylation as a housekeeping function, we identified an ER pathway that modulates the activity of OST-A. Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane receptors, and CCDC134, an ER luminal protein. During its translocation into the ER, an N-terminal peptide in HSP90B1 templates the assembly of a translocon complex containing CCDC134 and OST-A that protects HSP90B1 during folding, preventing its hyperglycosylation and degradation. Disruption of this pathway impairs WNT and IGF1R signaling and causes the bone developmental disorder osteogenesis imperfecta. Thus, N-glycosylation can be regulated by specificity factors in the ER to control cell surface receptor signaling and tissue development.