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

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

doi:10.1016/j.celrep.2018.04.063

Melissa J Silvestrini, Joseph R Johnson + Show 8 more

Open Access

https://doi.org/10.1016/j.celrep.2018.04.063

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Journal: Cell Reports	Publication Date: May 1, 2018
Citations: 71	License type: CC BY 4.0

Affiliation: Brown University, Providence College

Abstract

SUMMARYTranscriptional 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 life-span 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.

Highlights

Autophagy is a conserved cellular mechanism required for longevity across phyla (Lapierre et al, 2015)
We find that genetic and pharmacological inhibition of XPO-1/XPO1 leads to the nuclear enrichment of HLH-30/transcription factor EB (TFEB) and mechanistic target of rapamycin (mTOR)-independent autophagic enhancement accompanied by conserved beneficial effects on proteostasis and lifespan
In order to systematically find new autophagy modulators, we performed a genome-wide RNAi screen and searched for genetic modifiers of the nuclear localization of HLH-30/ TFEB by following the distribution of HLH-30 fused to GFP (Lapierre et al, 2013a; Visvikis et al, 2014)

Summary

Introduction

Autophagy is a conserved cellular mechanism required for longevity across phyla (Lapierre et al, 2015). Functional HLH-30 is required for autophagy induction and life-span extension in multiple longevity models (Lapierre et al, 2013a) and mediates appropriate transcriptional response during starvation (O’Rourke and Ruvkun, 2013; Settembre et al, 2013), as well as heat stress and bacterial infection (Visvikis et al, 2014). We pursued an unbiased approach to find new regulators of the intracellular partitioning of HLH-30/TFEB and uncovered that the conserved gene Exportin-1 (xpo-1/XPO1) potently increases the nuclear enrichment of HLH-30/TFEB. We find that genetic and pharmacological inhibition of XPO-1/XPO1 leads to the nuclear enrichment of HLH-30/TFEB and mTOR-independent autophagic enhancement accompanied by conserved beneficial effects on proteostasis and lifespan

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