ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 02 2022
18 02 2022
Historique:
received:
11
08
2021
accepted:
26
01
2022
entrez:
19
2
2022
pubmed:
20
2
2022
medline:
5
3
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 35181679
doi: 10.1038/s41467-022-28599-9
pii: 10.1038/s41467-022-28599-9
pmc: PMC8857226
doi:
Substances chimiques
Caenorhabditis elegans Proteins
0
Activating Transcription Factor 4
145891-90-3
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Hydrogen Sulfide
YY9FVM7NSN
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
967Subventions
Organisme : NCRR NIH HHS
ID : S10 RR028832
Pays : United States
Organisme : NIH HHS
ID : P40 OD010440
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054215
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK036836
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122610
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
pubmed: 20336132
doi: 10.1038/nature08980
Blackwell, T. K., Sewell, A. K., Wu, Z. & Han, M. TOR Signaling in Caenorhabditis elegans development, metabolism, and aging. Genetics 213, 329–360 (2019).
pubmed: 31594908
pmcid: 6781902
doi: 10.1534/genetics.119.302504
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
pubmed: 31937935
pmcid: 7102936
doi: 10.1038/s41580-019-0199-y
Ben-Sahra, I. & Manning, B. D. mTORC1 signaling and the metabolic control of cell growth. Curr. Opin. Cell Biol. 45, 72–82 (2017).
pubmed: 28411448
pmcid: 5545101
doi: 10.1016/j.ceb.2017.02.012
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
pubmed: 20074526
pmcid: 2824086
doi: 10.1016/j.cmet.2009.11.010
Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
pubmed: 22560223
pmcid: 3348514
doi: 10.1016/j.cmet.2012.04.007
Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (2007).
pubmed: 17266680
doi: 10.1111/j.1474-9726.2006.00266.x
Curran, S. P. & Ruvkun, G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56 (2007).
pubmed: 17411345
pmcid: 1847696
doi: 10.1371/journal.pgen.0030056
Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445, 922–926 (2007).
pubmed: 17277769
doi: 10.1038/nature05603
Wang, J. et al. RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet. 6, https://doi.org/10.1371/journal.pgen.1001048 (2010).
Howard, A. C., Rollins, J., Snow, S., Castor, S. & Rogers, A. N. Reducing translation through eIF4G/IFG-1 improves survival under ER stress that depends on heat shock factor HSF-1 in Caenorhabditis elegans. Aging Cell 15, 1027–1038 (2016).
pubmed: 27538368
pmcid: 5114698
doi: 10.1111/acel.12516
Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).
pubmed: 17266679
doi: 10.1111/j.1474-9726.2006.00267.x
Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).
pubmed: 12667446
doi: 10.1016/S1097-2765(03)00105-9
Costa-Mattioli, M. & Walter, P. The integrated stress response: from mechanism to disease. Science 368, https://doi.org/10.1126/science.aat5314 (2020).
Derisbourg, M. J., Wester, L. E., Baddi, R. & Denzel, M. S. Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation. Nat. Commun. 12, 1678 (2021).
pubmed: 33723245
pmcid: 7960713
doi: 10.1038/s41467-021-21743-x
Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife 2, e00498 (2013).
pubmed: 23741617
pmcid: 3667625
doi: 10.7554/eLife.00498
Mittal, N. et al. The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan. Nat. Commun. 8, 457 (2017).
pubmed: 28878244
pmcid: 5587724
doi: 10.1038/s41467-017-00539-y
Hu, Z. et al. Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan. Elife 7, https://doi.org/10.7554/eLife.35551 (2018).
Horn, M. et al. Hexosamine pathway activation improves protein homeostasis through the integrated stress response. iScience 23, 100887 (2020).
pubmed: 32086012
pmcid: 7033349
doi: 10.1016/j.isci.2020.100887
Park, Y., Reyna-Neyra, A., Philippe, L. & Thoreen, C. C. mTORC1 Balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4. Cell Rep. 19, 1083–1090 (2017).
pubmed: 28494858
pmcid: 5811220
doi: 10.1016/j.celrep.2017.04.042
Rousakis, A. et al. The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans. Aging Cell 12, 742–751 (2013).
pubmed: 23692540
doi: 10.1111/acel.12101
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
pubmed: 27629041
pmcid: 5048378
doi: 10.15252/embr.201642195
Kulalert, W., Sadeeshkumar, H., Zhang, Y. K., Schroeder, F. C. & Kim, D. H. Molecular determinants of the regulation of development and metabolism by neuronal eIF2alpha phosphorylation in Caenorhabditis elegans. Genetics 206, 251–263 (2017).
pubmed: 28292919
pmcid: 5419473
doi: 10.1534/genetics.117.200568
Li, W. J. et al. Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans. Nat. Commun. 12, 4568 (2021).
pubmed: 34315882
pmcid: 8316574
doi: 10.1038/s41467-021-24816-z
Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y. & Isik, M. SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic. Biol. Med. 88, 290–301 (2015).
pubmed: 26232625
pmcid: 4809198
doi: 10.1016/j.freeradbiomed.2015.06.008
Ewald, C. Y., Landis, J. N., Porter Abate, J., Murphy, C. T. & Blackwell, T. K. Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519, 97–101 (2015).
pubmed: 25517099
doi: 10.1038/nature14021
Quiros, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 216, 2027–2045 (2017).
pubmed: 28566324
pmcid: 5496626
doi: 10.1083/jcb.201702058
Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).
pubmed: 23624402
pmcid: 3692270
doi: 10.1038/ncb2738
Hoshino, A. et al. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature 575, 375–379 (2019).
pubmed: 31618756
pmcid: 6858570
doi: 10.1038/s41586-019-1667-4
Zhu, J. et al. Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab. 30, 865–876 (2019). e865.
pubmed: 31607565
pmcid: 6961654
doi: 10.1016/j.cmet.2019.09.009
Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005).
pubmed: 15924568
doi: 10.1111/j.1474-9726.2005.00152.x
Miller, D. L. & Roth, M. B. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 104, 20618–20622 (2007).
pubmed: 18077331
pmcid: 2154480
doi: 10.1073/pnas.0710191104
Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).
pubmed: 25542313
doi: 10.1016/j.cell.2014.11.048
Hammers, M. D. et al. A bright fluorescent probe for H2S enables analyte-responsive, 3D imaging in live zebrafish using light sheet fluorescence microscopy. J. Am. Chem. Soc. 137, 10216–10223 (2015).
pubmed: 26061541
pmcid: 4543995
doi: 10.1021/jacs.5b04196
Zivanovic, J. et al. Selective persulfide detection reveals evolutionarily conserved antiaging effects of s-sulfhydration. Cell Metab. 30, 1152–1170 (2019). e1113.
pubmed: 31735592
pmcid: 7185476
doi: 10.1016/j.cmet.2019.10.007
Paul, B. D. & Snyder, S. H. H2S: a novel gasotransmitter that signals by sulfhydration. Trends Biochem Sci. 40, 687–700 (2015).
pubmed: 26439534
pmcid: 4630104
doi: 10.1016/j.tibs.2015.08.007
Meng, J. et al. Global profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans. Nat. Commun. 12, 1415 (2021).
pubmed: 33658510
pmcid: 7930113
doi: 10.1038/s41467-021-21686-3
Molenaars, M. et al. A conserved mito-cytosolic translational balance links two longevity pathways. Cell Metab. 31, 549–563 (2020). e547.
pubmed: 32084377
pmcid: 7214782
doi: 10.1016/j.cmet.2020.01.011
Wei, Y. & Kenyon, C. Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 113, E2832–E2841 (2016).
pubmed: 27140632
pmcid: 4878494
doi: 10.1073/pnas.1524727113
Akaike, T. et al. Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat. Commun. 8, 1177 (2017).
pubmed: 29079736
pmcid: 5660078
doi: 10.1038/s41467-017-01311-y
Valvezan, A. J. & Manning, B. D. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333 (2019).
pubmed: 32694720
doi: 10.1038/s42255-019-0038-7
Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).
pubmed: 21376236
doi: 10.1016/j.cell.2011.02.014
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
pubmed: 16603397
doi: 10.1016/j.molcel.2006.03.029
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
pubmed: 22461615
pmcid: 3324089
doi: 10.1126/science.1215135
Rogers, A. N. et al. Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans. Cell Metab. 14, 55–66 (2011).
pubmed: 21723504
pmcid: 3220185
doi: 10.1016/j.cmet.2011.05.010
Li, W., Li, X. & Miller, R. A. ATF4 activity: a common feature shared by many kinds of slow-aging mice. Aging Cell 13, 1012–1018 (2014).
pubmed: 25156122
pmcid: 4326926
doi: 10.1111/acel.12264
Li, W. & Miller, R. A. Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J. Gerontol. A Biol. Sci. Med Sci. 70, 263–272 (2015).
pubmed: 24691093
doi: 10.1093/gerona/glu040
Hine, C., Zhu, Y., Hollenberg, A. N. & Mitchell, J. R. Dietary and endocrine regulation of endogenous hydrogen sulfide production: implications for longevity. Antioxid. Redox Signal 28, 1483–1502 (2018).
pubmed: 29634343
pmcid: 5930795
doi: 10.1089/ars.2017.7434
Heintz, C. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102–106 (2017).
pubmed: 27919065
doi: 10.1038/nature20789
Lee, G. et al. Post-transcriptional regulation of de novo lipogenesis by mTORC1-S6K1-SRPK2 signaling. Cell 171, 1545–1558.e18 (2017).
pubmed: 29153836
pmcid: 5920692
doi: 10.1016/j.cell.2017.10.037
Paul, B. D. & Snyder, S. H. H
pubmed: 22781905
doi: 10.1038/nrm3391
Filipovic, M. R., Zivanovic, J., Alvarez, B. & Banerjee, R. Chemical biology of H
pubmed: 29112440
doi: 10.1021/acs.chemrev.7b00205
Longchamp, A. et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H
pubmed: 29570992
pmcid: 5901681
doi: 10.1016/j.cell.2018.03.001
Islam, K. N., Polhemus, D. J., Donnarumma, E., Brewster, L. P. & Lefer, D. J. Hydrogen sulfide levels and nuclear factor-erythroid 2-related factor 2 (NRF2) activity are attenuated in the setting of critical limb ischemia (CLI). J. Am. Heart Assoc. 4, https://doi.org/10.1161/JAHA.115.001986 (2015).
Venz, R., Korosteleva, A., Jongsma, E. & Ewald, C. Y. Combining auxin-induced degradation and RNAi screening identifies novel genes involved in lipid bilayer stress sensing in Caenorhabditis elegans. G3 (Bethesda) 10, 3921–3928 (2020).
doi: 10.1534/g3.120.401635
Ewald, C. Y. et al. NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans. Elife 6, https://doi.org/10.7554/eLife.19493 (2017).
Schmidt, E. K., Clavarino, G., Ceppi, M. & Pierre, P. SUnSET, a nonradioactive method to monitor protein synthesis. Nat. Methods 6, 275–277 (2009).
pubmed: 19305406
doi: 10.1038/nmeth.1314
Steinbaugh, M. J. et al. Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. Elife 4, https://doi.org/10.7554/eLife.07836 (2015).
Kim, W., Underwood, R. S., Greenwald, I. & Shaye, D. D. OrthoList 2: a new comparative genomic analysis of human and Caenorhabditis elegans genes. Genetics 210, 445–461 (2018).
pubmed: 30120140
pmcid: 6216590
doi: 10.1534/genetics.118.301307
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197
Stroustrup, N. et al. The Caenorhabditis elegans lifespan machine. Nat. Methods 10, 665–670 (2013).
pubmed: 23666410
pmcid: 3865717
doi: 10.1038/nmeth.2475
Gentleman, R. Ia. R. R: a language for data analysis and graphics. J. Computat. Graph. Stat. 5, 299–314 (1996).
Ewald, C. Y., Hourihan, J. M. & Blackwell, T. K. Oxidative Stress Assays (arsenite and tBHP) in Caenorhabditis elegans. Bio. Protoc. 7, https://doi.org/10.21769/BioProtoc.2365 (2017).
Takai, Y. & Asami, T. Formation of methyl mercaptan in paddy soils I. Soil Sci. Plant Nutr. 8, 40–44 (1962).
doi: 10.1080/00380768.1962.10430996
Farbood, M. I. & MacNEIL, J. H. Limitations of lead acetate for separation of methanethiol and hydrogen sulfide from food systems. J. Food Sci. 43, 139–140 (1978).
doi: 10.1111/j.1365-2621.1978.tb09753.x
Dateo, G. P., Clapp, R. C., Mackey, D. A. M., Hewitt, E. J. & Hasselstrom, T. Identification of the volatile sulfur components of cooked cabbage and the nature of the precursors in the fresh vegetable. J. Food Sci. 22, 440–447 (1957).
doi: 10.1111/j.1365-2621.1957.tb17501.x
Teuscher, A. C. & Ewald, C. Y. Overcoming autofluorescence to assess GFP expression during normal physiology and aging in Caenorhabditis elegans. Bio. Protoc. 8, https://doi.org/10.21769/BioProtoc.2940 (2018).
Hourihan, J. M., Moronetti Mazzeo, L. E., Fernandez-Cardenas, L. P. & Blackwell, T. K. Cysteine sulfenylation directs IRE-1 to activate the SKN-1/Nrf2 antioxidant response. Mol. Cell 63, 553–566 (2016).
pubmed: 27540856
pmcid: 4996358
doi: 10.1016/j.molcel.2016.07.019
Stadler, M., Artiles, K., Pak, J. & Fire, A. Contributions of mRNA abundance, ribosome loading, and post- or peri-translational effects to temporal repression of C. elegans heterochronic miRNA targets. Genome Res. 22, 2418–2426 (2012).
pubmed: 22855835
pmcid: 3514671
doi: 10.1101/gr.136515.111