Regulated 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 by specificity factors in the ER to control cell surface receptor signaling and tissue development.
Authors
- Valérie Cormier‐Daire (ORCID: https://orcid.org/0000-0002-2839-9856)
- Juliette Fédry (ORCID: https://orcid.org/0000-0002-6592-4269)
- Katherine A. Overmyer (ORCID: https://orcid.org/0000-0002-1929-1229)
- L. Aravind (ORCID: https://orcid.org/0000-0003-0771-253X)
- Rajat Rohatgi (ORCID: https://orcid.org/0000-0001-7609-8858)
- Evgenia Shishkova (ORCID: https://orcid.org/0000-0001-6097-6097)
- Ganesh V. Pusapati (ORCID: https://orcid.org/0000-0002-1406-2566)
- Annie Jen (ORCID: https://orcid.org/0000-0001-5569-8387)
- Ramin Dubey (ORCID: https://orcid.org/0000-0002-0687-5831)
- Mengxiao Ma (ORCID: https://orcid.org/0000-0003-4166-6004)
- Joshua J. Coon (ORCID: https://orcid.org/0000-0002-0004-8253)
Institutions
- Hôpital Necker-Enfants Malades (FR)
- University of Wisconsin–Madison (US)
- Inserm (FR)
- MRC Laboratory of Molecular Biology (GB)
- Université Paris Cité (FR)
- United States National Library of Medicine (US)
- Morgridge Institute for Research (US)
- Institut Necker Enfants Malades (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Quantitative BioSciences (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1126/science.adp7201
- Citations
- 19
- Primary Topic
- Galectins and Cancer Biology
- Type
- article
- Field-Weighted Citation Impact
- 4.57
Funders
- A.P. Giannini Foundation
- Jean Perkins Foundation
- Giannini Foundation of Agricultural Economics
- Fondation Philanthropia
- National Institutes of Health
- Medical Research Council