Imaging within single NPCs reveals NXF1’s role in mRNA export on the cytoplasmic side of the pore

Ben-Yishay, Rakefet; Mor, Amir; Shraga, Amit; Ashkenazy-Titelman, Asaf; Kinor, Noa; Schwed-Gross, Avital; Jacob, Avi; Kozer, Noga; Kumar, Pramod; Garini, Yuval; Shav‐Tal, Yaron

doi:10.1083/jcb.201901127

Cited by 29 publications

(35 citation statements)

References 83 publications

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“…Furthermore, the interaction of Mex67 with the NPC is not modulated by the DEAD-box ATPase Dbp5. These findings are consistent with a recent report in mammalian cells (Ben-Yishay et al, 2019). Since Dbp5 is thought to impart directionality to the mRNA export process by releasing export factors form cargo, this suggests that the action of Dbp5 leads to the release of mRNA from Mex67 but not of Mex67 from the NPC.…”

Section: Resultssupporting

confidence: 93%

The RNA export factor Mex67 functions as a mobile nucleoporin

Derrer

Mancini

Vallotton

et al. 2019

Preprint

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The RNA export factor Mex67 is essential for the transport of mRNA through the nuclear pore complex (NPC) in yeast, but the molecular mechanism of this export process remains poorly understood. Here, we use quantitative fluorescence microscopy techniques in live budding yeast cells to investigate how Mex67 facilitates mRNA export. We show that Mex67 exhibits little interaction with mRNA in the nucleus and localizes to the NPC independently of mRNA, occupying a set of binding sites offered by FG repeats in the NPC. The ATPase Dbp5, which is thought to remove Mex67 from transcripts, does not affect the interaction of Mex67 with the NPC. Strikingly, we find that the essential function of Mex67 is spatially restricted to the NPC since a fusion of Mex67 to the nucleoporin Nup116 rescues a deletion of MEX67. Thus, Mex67 functions as a mobile nuclear pore component, which receives mRNA export substrates in the central channel of the NPC to facilitate their translocation to the cytoplasm.nuclear pore complex | mRNA export | Mex67 | Dbp5 | FCS

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Section: Resultssupporting

confidence: 93%

The RNA export factor Mex67 functions as a mobile nucleoporin

Derrer

Mancini

Vallotton

et al. 2019

Preprint

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“…Moreover, we found that DDX19B and NXF1 share the same network of proteinprotein interactions with a high confidence value (0.884) ( Figure 5D). It was suggested that in human cells DDX19B functions on the cytoplasmic side of the nuclear pore complex and is required for the final release of mRNA from NXF1 into the cytoplasm [22]. All this evidence strongly supports a possible correlation between the cytosolic transport of the nuclear uc.8+ during the tumor and/or cell life, with a cytosolic role of this lncRNA in order to fulfill its cellular functions.…”

Section: Prediction Of Uc8+ Interactions In Bladder Cancermentioning

confidence: 82%

“…In particular, we aligned the uc.8+ nucleotide sequence to the Ensembl transcript annotation database. The deep learning analysis identified 46 sequences spread in 45 genes, with an average length of about 19 bp (in the range [17][18][19][20][21][22][23][24][25][26][27]. The results of the deep learning analysis for the subcellular localization of uc.8+ indicated a prevalence of lncRNA sequences located at nuclear sites (Figure 2A).…”

Section: In Silico Analysis Indicates That Uc8+ Has Both Nuclear Andmentioning

confidence: 99%

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue

Terreri

Mancinelli

Ferro

et al. 2021

Cancers

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Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.

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“…This raises interesting questions regarding the functional relationship of TPR and NXF1 at NPCs. Notably, recent reports suggest that NXF1-binding sites within the NPC are not closely adjacent to TPR and that NXF1 occupies sites on the cytoplasmic side of the NPC 42 . Consistent with this report, our findings indicate that NXF1 association with NPCs is independent of TPR, and we speculate that loss of TPR phenocopies loss of NXF1 because NXF1 operates upstream of both TPR and GANP at early steps of mRNA processing 1 .…”

Section: Discussionmentioning

confidence: 99%

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

et al. 2020

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Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we apply an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in transcriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover.

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Imaging within single NPCs reveals NXF1’s role in mRNA export on the cytoplasmic side of the pore

Cited by 29 publications

References 83 publications

The RNA export factor Mex67 functions as a mobile nucleoporin

The RNA export factor Mex67 functions as a mobile nucleoporin

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue

Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

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