biostudies-literatureMa MNICHD NIH HHSMedical Research CouncilNIGMS NIH HHS667-672https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617332biostudies-literatureUnknown386(6722)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 byScience (New York, N.Y.)Regulated N-glycosylation controls chaperone function and receptor trafficking.PMC7617332R35 GM118082MC_UP_1201/32P41 GM108538R21 HD101980R01 HD113790Overmyer KASingal BFedry JDubey RCormier-Daire VMa MJen AShishkova EAravind LPusapati GVRohatgi RCoon JJfalseRegulated N-glycosylation controls chaperone function and receptor trafficking.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 by2024-01-01T00:00:00Z2024 Nov2025-04-04T02:23:21.151Z2025-04-04T02:23:21.151ZS-EPMC76173323950950710.1126/science.adp7201