FOXO and HSF1 rejuvenate immunity via positive feedback regulation of insulin/IGF-1 signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA573686 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10164061_1.fastq.gz | Fastqsanger.gz | |||
| SRR10164061_2.fastq.gz | Fastqsanger.gz | |||
| SRR10164062_1.fastq.gz | Fastqsanger.gz | |||
| SRR10164062_2.fastq.gz | Fastqsanger.gz | |||
| SRR10164063_1.fastq.gz | Fastqsanger.gz |
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Project description:A hallmark of aging is immunosenescence, a decline in immune function that appeared to be inevitable. Surprisingly, here we show that genetic inhibition of DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and even rejuvenates immunity in C. elegans. We find that p38 mitogen activated protein kinase (PMK-1), a key determinant of immunosenescence in wild-type, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of zip-10/bZip transcription factor, which in turn down-regulates ins-7, an agonistic insulin-like peptide, for further reduction in insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via up-regulating anti-aging transcription factors that regulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to developing strategies for immune rejuvenation in humans.
2021-02-26 | GSE137861 | GEO
Project description:Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified JMJD6 as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a non-canonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces HSP70 R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role for cellular adaptation to proteotoxic stress.
2024-07-18 | GSE270672 | GEO
Project description:Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified JMJD6 as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a non-canonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces HSP70 R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role for cellular adaptation to proteotoxic stress.
2024-07-18 | GSE270671 | GEO
Project description:Whole fly transcript profiles of changes upon induction of dFOXO in the gut and fat body using S1106>dFOXO flies and how this response changes when the feedback to foxo is removed in the foxo null background
2014-02-05 | E-MTAB-1232 | biostudies-arrayexpress
Project description:The heat shock response is a universal transcriptional response to proteotoxic stress orchestrated by heat shock transcription factor Hsf1 in all eukaryotic cells. Despite over 40 years of intense research, the mechanism of HSF1 activity regulation remains poorly understood at a molecular level. In metazoa Hsf1 trimerizes upon heat shock through a leucin-zipper domain and binds to DNA. How Hsf1 is dislodged from DNA and monomerized remained enigmatic. Here, using purified proteins we demonstrate that unmodified trimeric Hsf1 is dissociated from DNA in vitro by Hsc70 and DnaJB1. Hsc70 binds to multiple sites in Hsf1 with different affinities. Hsf1 trimers are monomerized by successive cycles of entropic pulling, unzipping the triple leucinezipper. Starting this unzipping at several protomers of the Hsf1 trimer results in faster monomerization. This process directly monitors the concentration of Hsc70 and DnaJB1. During heat shock adaptation Hsc70 first binds to a high affinity site in the transactivation domain leading to partial attenuation of the response and subsequently, at higher concentrations, Hsc70 removes Hsf1 from DNA to restore the resting state.
2020-06-22 | PXD017406 | Pride
Project description:Upon heat shock, Hsf1 protein is extensively phosphorylated, however, this modification is inhibited by an hsf1-bal mutation. To get genome-wide effect of the hyperphosphorylation on Hsf1-regulated transcription, the heat-induced gene expression profiles in HSF1 and hsf1-bal cells were compared. Keywords: stress response
2005-09-27 | GSE3361 | GEO
Project description:Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating and manifesting changes to metabolism and behavior across generations remain scarce. By employing a multigenerational starvation paradigm in C. elegans, we show that starvation-induced changes in DAF-16/FoxO activity, the main downstream target of insulin/IGF-1 receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points further demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.
2023-03-09 | GSE198939 | GEO
Project description:Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. InCaenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.
2023-10-04 | GSE244495 | GEO
Project description:Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (MIRKO) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (QKO). Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in MIGIRKO muscle, and these were reversed with FoxO knockout. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.
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