Regulated N-glycosylation controls chaperone function and receptor trafficking

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-11-07 DOI:10.1126/science.adp7201

Mengxiao Ma, Ramin Dubey, Annie Jen, Ganesh V. Pusapati, Bharti Singal, Evgenia Shishkova, Katherine A. Overmyer, Valérie Cormier-Daire, Juliette Fedry, L. Aravind, Joshua J. Coon, Rajat Rohatgi

引用次数: 0

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.

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受调控的 N-糖基化控制着伴侣功能和受体迁移

五分之一的人类蛋白质在内质网（ER）中由两种寡糖转移酶 OST-A 和 OST-B 进行 N-糖基化。与普遍认为 N-糖基化是一种看家功能的观点相反，我们发现了一种调节 OST-A 活性的 ER 通路。遗传分析将 OST-A 与 HSP90B1（一种用于膜受体的 ER 合子）和 CCDC134（一种 ER 管腔蛋白）联系起来。HSP90B1在转运到ER的过程中，其N端肽会模板化一个包含CCDC134和OST-A的转运体复合物，在折叠过程中保护HSP90B1，防止其过度糖基化和降解。这一途径的中断会影响 WNT 和 IGF1R 信号的传递，并导致骨骼发育障碍性成骨不全症。因此，N-糖基化可由ER中的特异性因子调控，从而控制细胞表面受体信号传导和组织发育。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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