O-GlcNAc modulation of nuclear pore complexes orchestrates mRNA export efficiency

• 成果类型: Article
• 署名作者: Junod, Samuel L.; Rush, Coby; Tingey, Mark; Yang, Weidong
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9173
• DOI: 10.1073/pnas.2502687122
• 发表日期: 2025-08-12
• 关键词: linked n-acetylglucosamine; modified proteins; gicnac modification; glcnacylation; glycosylation; transferase; nucleoporins; phosphorylation; identification; inhibitor

摘要

Efficient gene expression depends on the tightly regulated export of messenger RNA (mRNA) through nuclear pore complexes (NPCs), which are densely modified by O-linked N-acetylglucosamine (O-GlcNAc). Although dysregulated O-GlcNAcylation has been linked to a variety of human diseases, the precise distribution of O-GlcNAc within the NPC and its effects on mRNA export remain poorly understood. Here, we combined single-point edge-excitation subdiffraction (SPEED) microscopy with stochastic optical reconstruction microscopy (STORM) to map the nanometer-scale distribution of an O-GlcNAc analog (GlcNAz) within NPCs and to quantify the export kinetics of mRNA-protein complexes (mRNPs) under both normal and perturbed O-GlcNAcylation conditions. Under basal conditions, GlcNAz is predominantly localized around the central channel of the NPC. However, both hypo- and hyper-O-GlcNAcylation cause GlcNAz to redistribute toward the nuclear and cytoplasmic peripheries. This shift is paralleled by changes in mRNP localization and altered distributions of key, highly O-GlcNAcylated, phenylalanine-glycine nucleoporins. These architectural rearrangements are accompanied by functional consequences: Elevated O-GlcNAcylation nearly doubles mRNA export efficiency (similar to 61%), while reduced O-GlcNAcylation lowers it to similar to 16%, along with reduced NPC engagement. The transport receptor TAP exhibits analogous efficiency changes, reinforcing the role of O-GlcNAcylation as a key regulator of nucleocytoplasmic transport. Together, these results suggest that O-GlcNAcylation modulates NPC architecture and transport dynamics to fine-tune mRNA export, and indicate that targeted modulation of NPC O-GlcNAc levels may offer a promising strategy for addressing diseases associated with nuclear transport dysfunction.