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

Cell Reports
M J SilvestriniLouis R Lapierre

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.

Citations

Feb 12, 2020·Medicinal Research Reviews·Heike J WobstJames Shorter
Feb 13, 2020·Cells·Emiliano VicencioUte Woehlbier
May 31, 2019·Human Genetics·Shi Q WongLouis R Lapierre
Oct 20, 2018·Journal of Cell Science·Jhee Hong KohGuillaume Thibault
Aug 27, 2019·F1000Research·Robert Bayersdorf, Björn Schumacher
Nov 27, 2019·Nature Reviews. Molecular Cell Biology·Andrea Ballabio, Juan S Bonifacino
Sep 29, 2018·Molecular & Cellular Oncology·A V KumarL R Lapierre
Dec 11, 2020·ELife·Kathleen M CunninghamThomas E Lloyd
Dec 1, 2020·Molecular Oncology·Elena AstaninaGabriella Doronzo
Jan 9, 2021·EBioMedicine·Haocheng LuYanbo Fan
Jan 21, 2021·International Journal of Molecular Sciences·Shiyi Tan, Shi Chen
May 14, 2019·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Mark BouskaHua Bai
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Martina La SpinaJosé A Martina
Apr 23, 2021·Chembiochem : a European Journal of Chemical Biology·Jeffrey G MartinDouglas S Johnson
Jul 30, 2021·Human Genomics·Nadia DehghaniRita Guerreiro
Aug 27, 2021·Oxidative Medicine and Cellular Longevity·Elisa Gorostieta-SalasSusana Castro-Obregón
Jul 7, 2020·Trends in Biochemical Sciences·Qian ZhaoMeng C Wang

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