ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_E5050F011EBF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.
Journal
Nature communications
Author(s)
Statzer C., Meng J., Venz R., Bland M., Robida-Stubbs S., Patel K., Petrovic D., Emsley R., Liu P., Morantte I., Haynes C., Mair W.B., Longchamp A., Filipovic M.R., Blackwell T.K., Ewald C.Y.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
18/02/2022
Peer-reviewed
Oui
Volume
13
Number
1
Pages
967
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H <sub>2</sub> S) production. This H <sub>2</sub> S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H <sub>2</sub> S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H <sub>2</sub> S levels, or enhancing mechanisms that H <sub>2</sub> S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.
Keywords
Activating Transcription Factor 4/genetics, Activating Transcription Factor 4/metabolism, Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins/genetics, Caenorhabditis elegans Proteins/metabolism, Hydrogen Sulfide/metabolism, Longevity/genetics, Mechanistic Target of Rapamycin Complex 1/metabolism, Signal Transduction/genetics
Pubmed
Web of science
Open Access
Yes
Create date
28/02/2022 10:41
Last modification date
23/11/2022 7:16
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