RRC ID 56223
Author Silvestrini MJ, Johnson JR, Kumar AV, Thakurta TG, Blais K, Neill ZA, Marion SW, St Amand V, Reenan RA, Lapierre LR.
Title Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan.
Journal Cell Rep
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.
Volume 23(7)
Pages 1915-1921
Published 2018-5-15
DOI 10.1016/j.celrep.2018.04.063
PII S2211-1247(18)30622-3
PMID 29768192
IF 7.815
Times Cited 13
C.elegans tm1978