Asparagine-linked glycosylation mediates glucose sensing for cell fate decision

ABSTRACT: Asparagine-linked glycosylation (N-glycosylation), a fundamental modification of proteins synthesized in the endoplasmic reticulum, is easily suppressed by glucose deprivation, but the role of this metabolic link has long remained unclear. We previously identified the activity of mannose metabolism, which branches from glycolysis, as a key determinant for N-glycosylation efficiency in glucose deprivation. Our genetic approach to uncouple mannose metabolism from glycolysis allowed the precise control of mannose metabolic activity via its salvage pathway, revealing that moderate decrease in N-glycosylation efficiency activated the pro-survival PERK-eIF2 signals, which enabled cells to safely cut metabolic costs in N-glycosylation to the minimal levels required for cell survival. In contrast, severe decrease in N-glycosylation efficiency sensitized lysosomes to external insults, thereby biasing cell fates to cell death. Moreover, we demonstrated the specific role of glucose metabolism in regulating global translation efficiency via LKB1. Our study reveals the unexpected role of N-glycosylation as a glucose-sensing mechanism.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Takehiro Suzuki  

LAB HEAD: Naoshi Dohmae

PROVIDER: PXD066382 | Pride | 2026-03-02

REPOSITORIES: Pride