The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans.
Autophagy is a cellular recycling process that has an important anti-aging role, but the underlying molecular mechanism is not well understood. The mammalian transcription factor EB (TFEB) was recently shown to regulate multiple genes in the autophagy process. Here we show that the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans and, in addition, has a key role in lifespan determination. We demonstrate that hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan. Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models and, notably, nuclear TFEB levels are augmented in the livers of mice subjected to dietary restriction, a known longevity-extending regimen. Collectively, our results demonstrate a conserved role for HLH-30 and TFEB in autophagy, and possibly longevity, and identify HLH-30 as a uniquely important transcription factor for lifespan modulation in Caenorhabditis elegans.
Program of Development and Aging, Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, USA.
Louis R
LR
Lapierre
C Daniel
CD
De Magalhaes Filho
Philip R
PR
McQuary
Chu-Chiao
CC
Chu
Orane
O
Visvikis
Jessica T
JT
Chang
Sara
S
Gelino
Binnan
B
Ong
Andrew E
AE
Davis
Javier E
JE
Irazoqui
Andrew
A
Dillin
Malene
M
Hansen
D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004032:Diet; D005260:Female; D008136:Longevity; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; C583069:HLH-30 protein, C elegans; C484068:Tcfeb protein, mouse