Journal
CELL REPORTS
Volume 23, Issue 7, Pages 1915-1921Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.04.063
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Funding
- RI-INBRE grant [P20 GM103430]
- NIH/NIA [R00 AG042494, R01 AG051810]
- American Federation for Aging Research
- Glenn Foundation for Medical Research Award for Research in Biological Mechanisms of Aging
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103430] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG051810, R00AG042494] Funding Source: NIH RePORTER
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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.
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