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

Cell Rep. 2018 May 15;23(7):1915-1921. doi: 10.1016/j.celrep.2018.04.063.

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.

Keywords: HLH-30; SINE; TFEB; XPO-1; XPO1; autophagy; longevity; lysosome; mTOR; nuclear export.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Humans
  • Longevity*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • Caenorhabditis elegans Proteins
  • HLH-30 protein, C elegans
  • TFEB protein, human