DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity

Lin, Xin-Xuan; Sen, Ilke; Janssens, Georges E.; Zhou, Xin; Fonslow, Bryan R.; Edgar, Daniel; Stroustrup, Nicholas; Swoboda, Peter; Yates, John R.; Ruvkun, Gary; Riedel, Christian G.

doi:10.1038/s41467-018-06624-0

Cited by 120 publications

(138 citation statements)

References 46 publications

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“…The analysis of pry-1 transcriptome revealed a significant number of aging-associated genes including IIS and UPR ER pathway components as well as those linked to lipid maintenance. Previous studies have shown that both, DAF-16 and XBP-1-mediated UPR ER signaling, regulate the stress response, lipid metabolism and longevity (Imanikia et al, 2019;Lee et al, 2003;Lin et al, 2018;Murphy et al, 2003;Taylor and Dillin, 2013). We also found that the expression of a significant number of DAF-16 direct targets was altered in pry-1 mutants and a majority of these were downregulated.…”

Section: Discussionsupporting

confidence: 61%

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Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

Mallick

Gupta

2020

Preprint

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Aging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). In C. elegans the key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. The pry-1 transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles and musclespecific overexpression of pry-1 extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.

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Section: Discussionsupporting

confidence: 61%

“…Thus, pry-1 appears to interact with multiple genetic networks. We also compared the pry-1 transcriptome with DE genes of the DAF-2-DAF-16 signaling pathway (Lin et al, 2018) and found a significant overlap (415 genes; R.F. :1.7, p< 2.228e-31, Table S3).…”

Section: Pry-1 Transcriptome Contains Genes Involved In Lifespan Regumentioning

confidence: 99%

Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

Mallick

Gupta

2020

Preprint

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“…We used daf-2 mutant animals expressing DAF-16::GFP, treated them with either control or smk-1 RNAi, and then subjected them to chromatin immunoprecipitation (ChIP)-seq analysis using an anti-GFP antibody. Looking across 2824 DAF-16 binding sites described in previous work 18 , we found no significant change in the binding of DAF-16 to its target regions (p = 0.152; Supplementary Fig. 4d; see also Supplementary Fig.…”

Section: Smk-1 Is Part Of a Nuclear Protein Phosphatase 4 Complexmentioning

confidence: 55%

DAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes

et al. 2020

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In C. elegans, the conserved transcription factor DAF-16/FOXO is a powerful aging regulator, relaying dire conditions into expression of stress resistance and longevity promoting genes. For some of these functions, including low insulin/IGF signaling (IIS), DAF-16 depends on the protein SMK-1/SMEK, but how SMK-1 exerts this role has remained unknown. We show that SMK-1 functions as part of a specific Protein Phosphatase 4 complex (PP4 SMK-1). Loss of PP4 SMK-1 hinders transcriptional initiation at several DAF-16-activated genes, predominantly by impairing RNA polymerase II recruitment to their promoters. Search for the relevant substrate of PP4 SMK-1 by phosphoproteomics identified the conserved transcriptional regulator SPT-5/SUPT5H, whose knockdown phenocopies the loss of PP4 SMK-1. Phosphoregulation of SPT-5 is known to control transcriptional events such as elongation and termination. Here we also show that transcription initiating events are influenced by the phosphorylation status of SPT-5, particularly at DAF-16 target genes where transcriptional initiation appears rate limiting, rendering PP4 SMK-1 crucial for many of DAF-16's physiological roles.

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“…In C. elegans, HLH-30 localizes to the nucleus in response to a variety of stresses such as germline removal, heat stress, and starvation ( Fig. S4 I) to ensure the transcriptional induction of many protective genes that function to induce lysosomal degradation pathways (Lapierre et al, 2013;Lin et al, 2018;O'Rourke and Ruvkun, 2013).…”

Section: Hlh-30/tfeb Regulates Mitochondrial Translation Inhibition-mmentioning

confidence: 99%

Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30

Liu

McIntyre

Janssens

et al. 2019

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AbstractMitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

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DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity

Cited by 120 publications

References 46 publications

Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

DAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes

Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30

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