Nucleocytoplasmic Shuttling of FTO Does Not Affect Starvation-Induced Autophagy.
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ABSTRACT:
SUBMITTER: Aas A
PROVIDER: S-EPMC5347998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gle1 is required for mRNA export in yeast and human cells. Here, we report that two human Gle1 (hGle1) isoforms are expressed in HeLa cells (hGle1A and B). The two encoded proteins are identical except for their COOH-terminal regions. hGle1A ends with a unique four-amino acid segment, whereas hGle1B has a COOH-terminal 43-amino acid span. Only hGle1B, the more abundant isoform, localizes to the nuclear envelope (NE) and pore complex. To test whether hGle1 is a dynamic shuttling transport factor, we microinjected HeLa cells with recombinant hGle1 and conducted photobleaching studies of live HeLa cells expressing EGFP-hGle1. Both strategies show that hGle1 shuttles between the nucleus and cytoplasm. An internal 39-amino acid domain is necessary and sufficient for mediating nucleocytoplasmic transport. Using a cell-permeable peptide strategy, we document a role for hGle1 shuttling in mRNA export. An hGle1 shuttling domain (SD) peptide impairs the export of both total poly(A)+ RNA and the specific dihydrofolate reductase mRNA. Coincidentally, SD peptide-treated cells show decreased endogenous hGle1 localization at the NE and reduced nucleocytoplasmic shuttling of microinjected, recombinant hGle1. These findings pinpoint the first functional motif in hGle1 and link hGle1 to the dynamic mRNA export mechanism.
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Project description:Gle1 is a nucleocytoplasmic shuttling protein with well-documented cytoplasmic roles as a modulator of ATP-dependent DEAD-box RNA helicases involved in messenger (m)RNA export, translation initiation and termination, and stress granule dynamics. Here, we identify a novel nuclear role for Gle1 during transcription termination. In HeLa cells treated with a peptide that disrupts Gle1 nucleocytoplasmic shuttling, we detected nuclear accumulation of specific mRNAs with elongated 3'-UTR (untranslated region). Enriched mRNAs were nascently transcribed and accumulated in the nucleus due to a change in transcription state and not due to altered nuclear export. Whereas Gle1 shuttling inhibition did not appear to perturb nuclear DDX19 functions, it did result in increased DDX1 nucleoplasmic localization and decreased DDX1 interactions with Gle1 and the pre-mRNA cleavage stimulation factor CstF-64. An increase in nuclear R-loop signal intensity was also observed with diminished Gle1 shuttling, as well as colocalization of Gle1 at R-loops. Taken together, these studies reveal a nuclear role for Gle1 in coordinating DDX1 function in transcription termination complexes.
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Project description:Gene expression in trypanosomes is controlled mostly by post-transcriptional pathways. Little is known about the components of mRNA nucleocytoplasmic export routes in these parasites. Comparative genomics has shown that the mRNA transport pathway is the least conserved pathway among eukaryotes. Nonetheless, we identified a RNA helicase (Hel45) that is conserved across eukaryotes and similar to shuttling proteins involved in mRNA export. We used in silico analysis to predict the structure of Trypanosoma cruzi Hel45, including the N-terminal domain and the C-terminal domain, and our findings suggest that this RNA helicase can form complexes with mRNA. Hel45 was present in both nucleus and cytoplasm. Electron microscopy showed that Hel45 is clustered close to the cytoplasmic side of nuclear pore complexes, and is also present in the nucleus where it is associated with peripheral compact chromatin. Deletion of a predicted Nuclear Export Signal motif led to the accumulation of Hel45ΔNES in the nucleus, indicating that Hel45 shuttles between the nucleus and the cytoplasm. This transport was dependent on active transcription but did not depend on the exportin Crm1. Knockdown of Mex67 in T. brucei caused the nuclear accumulation of the T. brucei ortholog of Hel45. Indeed, Hel45 is present in mRNA ribonucleoprotein complexes that are not associated with polysomes. It is still necessary to confirm the precise function of Hel45. However, this RNA helicase is associated with mRNA metabolism and its nucleocytoplasmic shuttling is dependent on an mRNA export route involving Mex67 receptor.
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