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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,12]]},"abstract":"<jats:p>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\u2013protein 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 (~61%), while reduced O-GlcNAcylation lowers it 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.<\/jats:p>","DOI":"10.1073\/pnas.2502687122","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T15:35:16Z","timestamp":1754580916000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["O-GlcNAc modulation of nuclear pore complexes orchestrates mRNA export efficiency"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4288-0240","authenticated-orcid":false,"given":"Samuel L.","family":"Junod","sequence":"first","affiliation":[{"name":"Department of Biology, Temple University","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9698-7355","authenticated-orcid":false,"given":"Coby","family":"Rush","sequence":"additional","affiliation":[{"name":"Department of Biology, Temple University","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-5585","authenticated-orcid":false,"given":"Mark","family":"Tingey","sequence":"additional","affiliation":[{"name":"Department of Biology, Temple University","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3649-1863","authenticated-orcid":false,"given":"Weidong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biology, Temple University","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c01006"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00974-7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1783"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.07.006"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-11-1146"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000526"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222278"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1704145115"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.6.2820"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.470047"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.06.013"},{"key":"e_1_3_4_12_2","first-page":"9266","article-title":"OGT restrains the expansion of DNA damage signaling","volume":"44","author":"Chen Q.","year":"2016","unstructured":"Q. 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