Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity
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ABSTRACT:
PROVIDER: PRJNA821910 | ENA |
REPOSITORIES: ENA
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Project description:Treating Saccharomyces cerevisiae cells with myriocin reduces the intracellular free pool of most amino acids. We find that transcriptional changes within the first 6 hours of drug treatment seem to have little impact on free pool changes. Rather the changes are driven early by post-translational events including impaired amino acid transporter activity, due to a reduced rate of sphingolipid biosynthesis, and an increased rate of endocytosis of at least some amino acid transporters, particularly the major methionine transporter Mup1.
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Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C. elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
2020-04-03 | GSE122457 | GEO
Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C.CaenorhabditisC. elegans elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
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Project description:Transcriptome analysis in HEK293T transfected with plasmid carrying different isoforms of BPIFB4 gene. This gene was previously associated with exceptional longevity in a GWAS study performed on three different populations. Results indicate an up-regulation of stress response genes and proteostasis genes in HEK293T transfected with plasmid carrying the longevity-associated variant (LAV) of BPIFB4. Total RNA obtained from HEK293T over-expressing wild-type or mutated form of BPIFB4.
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Project description:Endogenous siRNAs Promote Proteostasis and Longevity in Germline-less C. elegans
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Project description:The balance between protein synthesis and protein breakdown is known as protein homeostasis (proteostasis) and loss of proteostasis is one of the Hallmarks of Aging. The latter is maybe best illustrated by the fact that many age-related diseases like Parkinson’s and Alzheimer’s are characterized by the appearance of protein aggregates. However, very few studies actually measure protein half-life, and hence the observed lowered protein translation rates in many longevity models do not necessarily mean that the combined rate of synthesis and degradation (i.e. proteostasis) is lost or changed. To get a better insight in the actual changes in proteostasis of each protein in the proteome we have developed a quantitative mass-spectrometry based method that allows for the estimation of the half-life of each individual protein in the proteome and that is suitable for use in C. elegans. We have used this method to determine protein half-lives in developing C. elegans models of longevity and age-related disease and found that proteostasis, as measured by proteome-wide protein half-life is indeed dramatically changed in these models. However, the observed changes are in some cases unexpected and suggest that the combined rate of protein synthesis and breakdown does not necessarily correlate with eventual lifespan or healthspan. Furthermore, we show that the proteostasis network has a remarkable plasticity; in the tested models large changes in protein half-life are observed in the entire proteome rather than in a subset of proteins, thereby largely balancing the relative rate at which various biological processes proceed. Lastly, our data indicate that proteostasis is regulated at the level of the whole organism rather than at the single cell level. The here described method and observations are a start to further unravel how proteostasis and healthy aging are intertwined.
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Project description:Transcriptome analysis in HEK293T transfected with plasmid carrying different isoforms of BPIFB4 gene. This gene was previously associated with exceptional longevity in a GWAS study performed on three different populations. Results indicate an up-regulation of stress response genes and proteostasis genes in HEK293T transfected with plasmid carrying the longevity-associated variant (LAV) of BPIFB4.
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Project description:Impaired protein homeostasis promotes age-associated tissue dysregulation, presenting a need for therapeutic approaches that can restore proteome integrity. The heat shock factor HSF-1 is the master transcriptional regulator of proteostasis and regulates the expression of heat shock proteins (HSPs), which facilitate proper protein folding, localisation, and degradation. Increased HSF-1 activity can suppress proteotoxicity and enhance longevity across species. Studies into the mechanisms behind these beneficial effects have mostly focused on HSPs; however, the precise mechanisms by which increased HSF-1 activity extends lifespan are not known. To address this, we conducted an RNAi screen for genes that promote longevity, in C. elegans over expressing HSF-1 (hsf-1 OE). We found that ubiquilin-1 (ubql-1), a multifaceted shuttle protein that functions in protein degradation pathways is necessary for full lifespan extension in hsf-1OE worms. Surprisingly, we find that lack of ubql-1 does not impact proteostasis capacity, but does alter mitochondrial dynamics, in hsf-1 OE worms. These effects are independent of mitophagy or the mitochondrial unfolded protein response (mitoUPR) suggesting enhanced turnover of mitochondrial outer membrane proteins may be important for increased longevity via the HSF-1-ubiquilin-1 axis. Additionally, we reveal a role for ubql-1, a protein quality control regulator in regulating lipid homeostasis in hsf-1 OE animals. Lack of ubql-1 in hsf-1 OE animals supresses the expression of a key mitochondrial β-oxidation and lipid mobilization gene regulated by NHR-49 - acyl-CoA synthetase-2, ACS-2 amongst other genes. We propose that ubql-1 is required for mito-fusion and metabolic modulations that promote longevity in hsf-1 OE by interacting with NHR-49.
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