PQM-1 Complements DAF-16 as a Key Transcriptional Regulator of DAF-2-Mediated Development and Longevity

Tepper, Ronald G.; Ashraf, Jasmine; Kaletsky, Rachel; Kleemann, Gunnar; Murphy, Coleen T.; Bussemaker, Harmen J.

doi:10.1016/j.cell.2013.07.006

Cited by 261 publications

(476 citation statements)

References 46 publications

(96 reference statements)

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“…SWI/SNF chromatin remodeler and SKN-1/NRF2 are longevity factors that work together with DAF-16/FOXO (20)(21)(22). We identified significant overlaps between our hel-1-dependent up-regulated genes and genes up-regulated by SWI/SNF, DAF-16, or SKN-1 (Table 2) (20,21,23). Together these data suggest that HEL-1 regulates the induction of many DAF-16 target genes in daf-2 mutants.…”

Section: Hel-1 Extends Lifespan By the Induction Of Daf-16/foxo-depensupporting

confidence: 48%

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Seo

Hwang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans.arious genetic and environmental factors, including insulin/ insulin-like growth factor 1 (IGF-1) signaling (IIS), target of rapamycin signaling, dietary restriction, mitochondrial respiration, and reproductive systems, influence aging across phyla (reviewed in refs. 1-3). IIS is one of the most evolutionarily conserved pathways involved in the regulation of aging. Mutations in Caenorhabditis elegans daf-2, which encodes an insulin/IGF-1 receptor homolog, double the lifespan of C. elegans (4). Inhibition of DAF-2 reduces phosphatidylinositide 3 (PI3)-kinase signaling, which upregulates several transcription factors, including DAF-16/forkhead box O (FOXO), heat shock factor-1 (HSF-1), and SKN-1/NRF2 (reviewed in refs. 1, 3, and 5). DAF-16 is one of the best characterized of these longevity factors; reduced PI3-kinase signaling leads to the dephosphorylation and nuclear translocation of DAF-16, which up-regulates the expression of various target genes. DAF-16 target genes contribute to longevity by promoting stress resistance, reproductive span, innate immunity, and protein homeostasis.RNA helicases are essential for biogenesis, maturation, processing, and homeostasis of various types of RNAs (reviewed in ref. 6). In addition, RNA helicases work with factors, such as a CREBbinding protein, RNA polymerases I and II, and histone deacetylases, to regulate transcriptional activity (7,8). For example, DDX5 (p68), a DEAD-box RNA helicase, interacts with Smad3, a transcriptional activator and intracellular effector of TGF-β (9), and with RNA polymerase II to modulate transcriptional activity (10). Because RNA helicases comprise a large family of housekeeping proteins essential for RNA biogenesis and homeostasis, their importanc...

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Section: Hel-1 Extends Lifespan By the Induction Of Daf-16/foxo-depensupporting

confidence: 48%

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Seo

Hwang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Equilibrium between verylong and long-chain ceramides is also thought to be important for normal cellular physiology (Grosch et al 2012). (Tepper et al 2013). The lists of overlapping genes are included in Table S2, B and C. The statistical significance of the overlap is presented in Table S4.…”

Section: Discussionmentioning

confidence: 99%

“…The comparison between CerS(rf) affected genes and daf-16/FOXO responsive genes (Murphy et al 2003;Tepper et al 2013) identified 139 overlapping genes, which is 2.5-fold higher than expected by chance (P , 1.66 e 230 ) (Figure 4B, Table S2, B and C, and Table S4). Among these 139 genes, 92 are repressed by daf-16/FOXO, and 47 are upregulated by daf-16/FOXO.…”

Section: Ceramide Affects the Expression Of Daf-16/foxo-and Rb-regulamentioning

confidence: 99%

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Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

et al. 2017

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Our understanding of the cellular mechanisms by which animals regulate their response to starvation is limited, despite the strong relevance of the problem to major human health issues. The L1 diapause of Caenorhabditis elegans, where first-stage larvae arrest in response to a food-less environment, is an excellent system to study this mechanism. We found, through genetic manipulation and lipid analysis, that biosynthesis of ceramide, particularly those with longer fatty acid side chains, critically impacts animal survival during L1 diapause. Genetic interaction analysis suggests that ceramide may act in both insulin-IGF-1 signaling (IIS)-dependent and IISindependent pathways to affect starvation survival. Genetic and expression analyses indicate that ceramide is required for maintaining the proper expression of previously characterized starvation-responsive genes, genes that are regulated by the IIS pathway and tumor suppressor Rb, and genes responsive to pathogen. These findings provide an important insight into the roles of sphingolipid metabolism, not only in starvation response, but also in aging and food-response-related human health problems.

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“…Genetic studies in Caenorhabditis elegans suggest that DAF-16, the Foxo ortholog, functions as a transcriptional activator downstream of the insulin/IGF-1 signaling pathway but does not bind to the promoter of repressed genes. Rather, genes that are down-regulated by DAF-16 (class II genes) are more likely indirect targets and regulated by the induction of a repressor protein by DAF-16 (43)(44)(45). Tepper et al (45) recently described an elusive transcriptional activator, PQM-1, that is mutually antagonistic with DAF-16 with regard to subcellular localization in response to insulin/ IGF-1 signaling, providing a mechanism for the regulation of Class II genes.…”

Section: Discussionmentioning

confidence: 99%

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

Chen

Lu²,

Monks³

et al. 2016

Journal of Biological Chemistry

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Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression.

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PQM-1 Complements DAF-16 as a Key Transcriptional Regulator of DAF-2-Mediated Development and Longevity

Cited by 261 publications

References 46 publications

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein

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