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 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.