XBP1s activation can globally remodel N-glycan structure distribution patterns

Area of Science:

• Cellular Biology
• Glycobiology
• Molecular Biology

Background:

• The unfolded protein response (UPR) is crucial for maintaining proteostasis in the secretory pathway.
• The IRE1-activated spliced X-box binding protein 1 (XBP1s) pathway plays roles in secretory pathway maturation beyond stress response.
• Understanding XBP1s' cellular consequences is vital for development, immunity, and disease research.

Purpose of the Study:

• To investigate the functional outputs of XBP1s activation on cellular proteomes.
• To determine how XBP1s influences N-glycan structures on membrane and secreted proteins.
• To explore the mechanistic links between XBP1s and N-glycan remodeling.

Main Methods:

• Analysis of N-glycan structures on endogenous membrane and secreted proteomes in response to XBP1s activation.
• Cell type-specific proteomic and glycomic profiling (HEK293 and HeLa cells).
• mRNA profiling to identify transcriptional changes in N-glycan maturation pathways.

Main Results:

• XBP1s activation induces cell type-dependent shifts in N-glycan distribution.
• In HEK293 cells, XBP1s decreased sialylation and bisecting GlcNAc while increasing oligomannose N-glycans in the secretome.
• In HeLa cells, XBP1s increased high-mannose, tetraantennary N-glycans, and core fucosylation on membrane proteins.
• Transcriptional profiling suggests XBP1s coordinates N-glycan pathway remodeling.

Conclusions:

• XBP1s acts as a master regulator of N-glycan maturation.
• XBP1s-mediated N-glycan remodeling alters the molecular identity of cell surface and secreted proteins.
• This provides a novel mechanism linking intracellular stress signaling to extracellular interactions.