Reference - Detail
| RRC ID | 56223 |
|---|---|
| Author | Silvestrini MJ, Johnson JR, Kumar AV, Thakurta TG, Blais K, Neill ZA, Marion SW, St Amand V, Reenan RA, Lapierre LR. |
| Title | Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. |
| Journal | Cell Rep |
| Abstract |
Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models. Selective XPO1 inhibitors recapitulated the effect on autophagy and lifespan observed by silencing xpo-1 and protected ALS-afflicted flies from neurodegeneration. XPO1 inhibition in HeLa cells enhanced TFEB nuclear localization, autophagy, and lysosome biogenesis without affecting mTOR activity, revealing a conserved regulatory mechanism for HLH-30/TFEB. Altogether, our study demonstrates that altering the nuclear export of HLH-30/TFEB can regulate autophagy and establishes the rationale of targeting XPO1 to stimulate autophagy in order to prevent neurodegeneration. |
| Volume | 23(7) |
| Pages | 1915-1921 |
| Published | 2018-5-15 |
| DOI | 10.1016/j.celrep.2018.04.063 |
| PII | S2211-1247(18)30622-3 |
| PMID | 29768192 |
| PMC | PMC5991088 |
| MeSH | Active Transport, Cell Nucleus Animals Autophagy* Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism* Basic Helix-Loop-Helix Transcription Factors / metabolism* Caenorhabditis elegans / metabolism Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / metabolism* Cell Nucleus / metabolism* Gene Silencing HeLa Cells Humans Longevity* |
| IF | 7.815 |
| Times Cited | 13 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 50 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm1978 |