Regulated N-glycosylation controls chaperone function and receptor trafficking

• 成果类型: Article
• 署名作者: Ma, Mengxiao; Dubey, Ramin; Jen, Annie; Pusapati, Ganesh V.; Singal, Bharti; Shishkova, Evgenia; Overmyer, Katherine A.; Cormier-Daire, Valerie; Fedry, Juliette; Aravind, L.; Coon, Joshua J.; Rohatgi, Rajat
• 署名单位: Stanford University; Stanford University; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; The Morgridge Institute for Research, Inc.; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); MRC Laboratory Molecular Biology; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM); Division of Intramural Research (DIR); University of Wisconsin System; University of Wisconsin Madison
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11172
• DOI: 10.1126/science.adp7201
• 发表日期: 2024-11-08
• 页码: 667-672
• 关键词: oligosaccharyl transferase; grp94; protein; ccdc134; activation; subunits; abundant; roles

摘要

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.