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

Publication date: 15 May 2018
Source:Cell Reports, Volume 23, Issue 7
Author(s): Melissa J. Silvestrini, Joseph R. Johnson, Anita V. Kumar, Tara G. Thakurta, Karine Blais, Zachary A. Neill, Sarah W. Marion, Victoria St. Amand, Robert A. Reenan, Louis R. Lapierre
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.

Graphical abstract

Teaser

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.


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