| 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
|
| Resource |
| C.elegans |
tm1978 |
