Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan

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 enhanc...

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Published in:	Cell reports (Cambridge) Vol. 23; no. 7; pp. 1915 - 1921
Main Authors:	Silvestrini, Melissa J., Johnson, Joseph R., Kumar, Anita V., Thakurta, Tara G., Blais, Karine, Neill, Zachary A., Marion, Sarah W., St. Amand, Victoria, Reenan, Robert A., Lapierre, Louis R.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-05-2018
Subjects:	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 HLH-30 Humans Longevity lysosome mTOR nuclear export SINE TFEB XPO-1 XPO1 XPO1 autophagy nuclear export XPO-1 TFEB mTOR longevity SINE HLH-30 lysosome
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Summary:	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. [Display omitted] •Reducing XPO-1/XPO1 increases nuclear HLH-30/TFEB and stimulates autophagy•Lifespan extension by xpo-1 silencing mechanistically mimics longevity models•Selective inhibitors of nuclear export (SINEs) extend lifespan in worms and flies•SINEs enhance autophagy and lysosomal biogenesis without affecting mTOR signaling Nuclear enrichment of longevity-associated transcription factors is a conserved feature of multiple long-lived models. Silvestrini et al. show that selective inhibitors of nuclear export (SINEs) increase autophagy via HLH-30/TFEB nuclear enrichment, resulting in longer lifespan in nematodes and ALS-afflicted flies and autophagy/lysosomal enhancements in human cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact These authors contributed equally
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2018.04.063