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dc.contributor.authorStatzer, Cyril
dc.contributor.authorHaynes, Cole M
dc.contributor.authorBlackwell, T. Keith
dc.contributor.authorEwald, Collin Y.
dc.contributor.authorLiu, Pengpeng
dc.date2022-08-11T08:08:25.000
dc.date.accessioned2022-08-23T15:54:50Z
dc.date.available2022-08-23T15:54:50Z
dc.date.issued2020-11-02
dc.date.submitted2020-12-07
dc.identifier.citation<p>bioRxiv 2020.11.02.364703; doi: https://doi.org/10.1101/2020.11.02.364703. <a href="https://doi.org/10.1101/2020.11.02.364703" target="_blank" title="preprint in bioRxiv">Link to preprint on bioRxiv.</a></p>
dc.identifier.doi10.1101/2020.11.02.364703
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29629
dc.description<p>This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.</p> <p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractInhibition of mTORC1 (mechanistic target of rapamycin 1) slows ageing, but mTORC1 supports fundamental processes that include protein synthesis, making it critical to elucidate how mTORC1 inhibition increases lifespan. Under stress conditions, the integrated stress response (ISR) globally suppresses protein synthesis, resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that the ATF-4 transcription program promotes longevity and that ATF-4 upregulation mediates lifespan extension from mTORC1 inhibition. ATF-4 activates canonical anti-ageing mechanisms but also increases expression of transsulfuration enzymes to promote hydrogen sulfide (H2S) production. ATF-4-induced H2S production mediates longevity and stress resistance from C. elegans mTORC1 suppression, and ATF4 drives H2S production in mammalian dietary restriction. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. Increasing H2S levels, or enhancing mechanisms that H2S modulates through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR or mTORC1 inhibition.
dc.language.isoen_US
dc.relationNow published in Nature Communications, doi: https://doi.org/10.1038/s41467-022-28599-9
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectmRNA translation
dc.subjectcystathionine gamma-lyase
dc.subjectH2S
dc.subjectageing
dc.subjectmTORC1
dc.subjectIntegrated Stress Response
dc.subjectC. elegans
dc.subjectphysiology
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCellular and Molecular Physiology
dc.subjectEnzymes and Coenzymes
dc.subjectPhysiological Processes
dc.titleATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1 [preprint]
dc.typePreprint
dc.source.journaltitlebioRxiv
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2863&amp;context=faculty_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/1846
dc.identifier.contextkey20465027
refterms.dateFOA2022-08-23T15:54:50Z
html.description.abstract<p><p id="x-x-x-x-x-p-2">Inhibition of mTORC1 (mechanistic target of rapamycin 1) slows ageing, but mTORC1 supports fundamental processes that include protein synthesis, making it critical to elucidate how mTORC1 inhibition increases lifespan. Under stress conditions, the integrated stress response (ISR) globally suppresses protein synthesis, resulting in preferential translation of the transcription factor ATF-4. Here we show in <em>C. elegans</em> that the ATF-4 transcription program promotes longevity and that ATF-4 upregulation mediates lifespan extension from mTORC1 inhibition. ATF-4 activates canonical anti-ageing mechanisms but also increases expression of transsulfuration enzymes to promote hydrogen sulfide (H<sub>2</sub>S) production. ATF-4-induced H<sub>2</sub>S production mediates longevity and stress resistance from <em>C. elegans</em> mTORC1 suppression, and ATF4 drives H<sub>2</sub>S production in mammalian dietary restriction. This H<sub>2</sub>S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. Increasing H<sub>2</sub>S levels, or enhancing mechanisms that H<sub>2</sub>S modulates through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR or mTORC1 inhibition.</p>
dc.identifier.submissionpathfaculty_pubs/1846
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.