Regulated N-glycosylation controls chaperone function and receptor trafficking.

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• N-glycosylation is a crucial post-translational modification occurring in the endoplasmic reticulum (ER).
• It is catalyzed by oligosaccharyltransferases (OSTs), with OST-A and OST-B being key enzymes in humans.
• N-glycosylation was traditionally viewed as a general housekeeping process.

Purpose of the Study:

• To investigate novel regulatory mechanisms of N-glycosylation beyond its housekeeping role.
• To identify factors that modulate the activity of oligosaccharyltransferase A (OST-A).
• To understand the functional implications of regulated N-glycosylation in cellular processes and development.

Main Methods:

• Genetic analyses to identify interacting partners of OST-A.
• Investigating the role of ER chaperones and luminal proteins in N-glycosylation.
• Studying the impact of pathway disruption on WNT and IGF1R signaling pathways.
• Analyzing effects on bone development and the disorder osteogenesis imperfecta.

Main Results:

• A novel ER pathway was identified that modulates OST-A activity.
• Genetic studies linked OST-A to HSP90B1 and CCDC134.
• HSP90B1's N-terminal peptide templates a translocon complex with CCDC134 and OST-A, protecting HSP90B1 during folding.
• This complex prevents HSP90B1 hyperglycosylation and degradation.
• Disruption of this pathway leads to impaired WNT and IGF1R signaling.
• Pathway disruption is linked to osteogenesis imperfecta, a bone developmental disorder.

Conclusions:

• N-glycosylation is not solely a housekeeping function but is actively regulated in the ER.
• Specificity factors, such as CCDC134 and HSP90B1, play a role in controlling N-glycosylation.
• Regulated N-glycosylation is essential for proper cell surface receptor signaling.
• This regulation is critical for normal tissue development, as demonstrated by its role in bone formation.