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

Pengpeng Liu,Collin Y Ewald,Cyril Statzer,Cole Haynes,Dunja Petrovic,Richard Venz,Raffaella Emsley,Monet Bland,Alban Longchamp,Stacey Robida-Stubbs,Krina Patel,Milos R Filipovic,William B Mair,Jin Meng,Ianessa Morantte,T Keith Blackwell

doi:10.1038/s41467-022-28599-9

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.

Highlights

Inhibition of the master growth regulator mTORC1 slows ageing across phyla, in part by reducing protein synthesis
We investigated whether C. elegans atf-4 is regulated to mammalian ATF4 at the level of mRNA translation
Patf-4(uORF)::green fluorescent protein (GFP) expression was extremely low under unstressed conditions, but increased when translation was suppressed by treatment with the translation elongation blocker cycloheximide, or RNA interference (RNAi)-mediated knockdown of the tRNA synthase rars[1] (Fig. 1b, Supplementary Fig. 1c–f)

Summary

Introduction

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, and 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. Suppression of new protein synthesis is an important mechanism through which cells protect themselves from stressful conditions that include nutrient deprivation, and thermal-, oxidative-, and endoplasmic reticulum (ER) stress[13,14] Those stresses induce the evolutionarily conserved ISR by activating kinases that phosphorylate and inhibit the translation initiation factor subunit eIF2α, thereby imposing a broad reduction in capdependent mRNA translation[13,14]. The anti-ageing benefits of mTORC1 suppression depend upon this ATF-4-induced increase in H2S production, further supporting the idea that they derive from lower translation rates and suggesting that increases in ATF-4 and H2S levels may recapitulate these benefits

Methods

Results

Conclusion