RRC ID 76065
Author Statzer C, Meng J, Venz R, Bland M, Robida-Stubbs S, Patel K, Petrovic D, Emsley R, Liu P, Morantte I, Haynes C, Mair WB, Longchamp A, Filipovic MR, Blackwell TK, Ewald CY.
Title ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.
Journal Nat Commun
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 (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.
Volume 13(1)
Pages 967
Published 2022-2-18
DOI 10.1038/s41467-022-28599-9
PII 10.1038/s41467-022-28599-9
PMID 35181679
PMC PMC8857226
MeSH 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
Resource
C.elegans tm4397 tm4212