Eukaryotic cells respond to stress by reprogramming their gene expression program to inhibit global protein synthesis and direct translationally silenced mRNAs to cytoplasmic foci known as stress granules (SGs). SGs function as sites where mRNAs are sorted for storage, decay or translation. SGs are linked with neurodegeneration, cancer and viral infections. However, the molecular mechanisms underlying SG function during stress and in diseases are poorly understood. DEAD-box proteins (Dbps) are RNA-dependent ATPases that mediate changes in mRNA-protein complex (mRNP) structure. Several Dbps, including DDX3, are recruited to SGs and regulate mRNP entry and exit. But, it is unclear how the Dbp activity is regulated in SGs. In the work presented here, we show that human (h) Gle1 is a novel factor of SGs and it regulates SGs by modulating the dynamic equilibrium between SGs and translation through its regulation of DDX3. We further show that two alternatively spliced isoforms of the GLE1 gene perform distinct and non-overlapping functions in a cell; hGle1A is required for SG function, whereas hGle1B functions in SGs. Interestingly, our results also show that an amyotrophic lateral sclerosis (ALS)-linked mutation in GLE1 disrupts functional specificity of hGle1 isoforms and the resulting protein variant is bifunctional. Overall, this study provides insight into the critical roles of hGle1 in SG biology and also gives clues as to how mutation of GLE1 contributes towards ALS pathogenesis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09072016-140445 |
| Date | 12 September 2016 |
| Creators | Aditi, Aditi |
| Contributors | Dr. David M. Miller, Dr. Susan R. Wente, Dr. James R. Goldenring, Dr. Katherine L. Friedman, Dr. Nicholas J. Reiter |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-09072016-140445/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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