ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1

Statzer, Cyril; Liu, Pengpeng; Haynes, Cole M.; Blackwell, T. Keith; Ewald, Collin Y.

doi:10.1101/2020.11.02.364703

Cited by 11 publications

(19 citation statements)

References 100 publications

(292 reference statements)

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“…To test this hypothesis, we monitored the uORF-regulated translational activation of the worm homolog of GCN4/ATF4, atf-4 in the translational atf-4::GFP reporter strain. C. elegans atf-4 was previously named atf-5 33 . We used tunicamycin, a specific ER stress inducer that perturbs N-glycosylation, at varying doses to induce reporter expression.…”

Section: Resultsmentioning

confidence: 99%

Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

et al. 2021

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Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains poorly understood. Using a genomic mutagenesis screen for longevity in Caenorhabditis elegans, we define a role of eIF2 modulation in aging. By inhibiting the ISR, dominant mutations in eIF2B enhance protein homeostasis and increase lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolong lifespan. Lifespan extension through impeding the ISR occurs without a reduction in overall protein synthesis. Instead, we observe changes in the translational efficiency of a subset of mRNAs, of which the putative kinase kin-35 is required for lifespan extension. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.

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Section: Resultsmentioning

confidence: 99%

Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

et al. 2021

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“…However, phosphorylation of eIF2α also enables the selective translation of activating transcription factor 4 (ATF4), which upregulates a subset of UPR genes, including the apoptosis-inducing CCAAT/Enhancer Binding Protein (C/EBP) homologous protein ( CHOP ; also known as also known as growth arrest- and DNA damage-inducible gene 153, GADD153 ) and the growth arrest and DNA damage-inducible gene 34 ( GADD34 ) [ 35 ], restoring balance by dephosphorylating eIF2α [ 43 ]. Whereas the downstream actions of ATF4 are not well known in C. elegans , worm ATF-4 resembles human ATF4 in gene structure and regulation by upstream open reading frames [ 44 ] and in its response to general translational inhibition [ 45 ], implying strong functional similarity.…”

Section: The Animal Upr-er Is Composed Of Three Branchesmentioning

confidence: 99%

Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis

Taubert

2021

Metabolites

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Biological membranes are not only essential barriers that separate cellular and subcellular structures, but also perform other critical functions such as the initiation and propagation of intra- and intercellular signals. Each membrane-delineated organelle has a tightly regulated and custom-made membrane lipid composition that is critical for its normal function. The endoplasmic reticulum (ER) consists of a dynamic membrane network that is required for the synthesis and modification of proteins and lipids. The accumulation of unfolded proteins in the ER lumen activates an adaptive stress response known as the unfolded protein response (UPR-ER). Interestingly, recent findings show that lipid perturbation is also a direct activator of the UPR-ER, independent of protein misfolding. Here, we review proteostasis-independent UPR-ER activation in the genetically tractable model organism Caenorhabditis elegans. We review the current knowledge on the membrane lipid composition of the ER, its impact on organelle function and UPR-ER activation, and its potential role in human metabolic diseases. Further, we summarize the bi-directional interplay between lipid metabolism and the UPR-ER. We discuss recent progress identifying the different respective mechanisms by which disturbed proteostasis and lipid bilayer stress activate the UPR-ER. Finally, we consider how genetic and metabolic disturbances may disrupt ER homeostasis and activate the UPR and discuss how using -omics-type analyses will lead to more comprehensive insights into these processes.

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“…Another mechanism by which down-regulation of mTOR signaling leads to longevity, was presented by Collin Ewald, ETH Zurich, Switzerland. Collin"s team discovered a hydrogen sulfide pathway as a potential longevity mechanism that is up-regulated by ATF4 in dietary restriction (DR) as a stress response to a decrease in global mRNA translation [51]. Interestingly, hydrogen sulfide has already been shown to possess beneficial effects in age-related diseases with currently running clinical trials for cardio-vascular improvements (NCT02899364 and NCT02278276).…”

Section: Longevity Pathwaysmentioning

confidence: 99%