Substrate-directed control of N-glycosylation in the endoplasmic reticulum calibrates signal reception at the cell-surface

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 CCCD134, an ER protein we identify as the first specificity factor for N-glycosylation. During its translocation into the ER, a N-terminal peptide in HSP90B1 functions as a pseudosubstrate inhibitor of OST-A and templates the assembly of specialized ER translocon complexes containing CCDC134. Unexpectedly, OST-A functions as a scaffold rather than an enzyme in this context, stabilizing HSP90B1 by preventing its hyperglycosylation and degradation. Disruption of this pathway impairs WNT signaling at the cell surface and causes the bone developmental disorder Osteogenesis Imperfecta. Thus, N-glycosylation can be regulated by ER factors to control cell-surface receptor signaling and tissue development. One-Sentence SummaryN-glycosylation of asparagine residues on proteins can be regulated by specificity factors in the endoplasmic reticulum to control cell-surface signaling and tissue development.