Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm
Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm
BACKGROUND: The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered. RESULTS: We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner. CONCLUSION: DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity.
*Aging Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins/*metabolism Cell Nucleus/metabolism Cytoplasm/*metabolism Dose-Response Relationship, Drug Escherichia coli/metabolism Feedback, Physiological *Food Deprivation Forkhead Transcription Factors Gene Expression Regulation, Developmental Green Fluorescent Proteins/metabolism Hydrogen Peroxide/chemistry/pharmacology Inositol Phosphates/chemistry Mice Models, Biological Mutation Oxidative Stress Phosphatidylinositol 3-Kinases/*metabolism Polymerase Chain Reaction Protein Transport Temperature Time Factors Transcription Factors/*metabolism Transgenes
Weinkove, D.
639dac22-5adf-4692-87f6-f52dde0c0d95
Halstead, J. R.
019c9dab-c338-4f97-9318-353858ea82ac
Gems, D.
64f30241-6dab-4b23-af36-1e321fd317e7
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
3 February 2006
Weinkove, D.
639dac22-5adf-4692-87f6-f52dde0c0d95
Halstead, J. R.
019c9dab-c338-4f97-9318-353858ea82ac
Gems, D.
64f30241-6dab-4b23-af36-1e321fd317e7
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Weinkove, D., Halstead, J. R., Gems, D. and Divecha, N.
(2006)
Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm.
BMC Biology, 4.
(doi:10.1186/1741-7007-4-1).
Abstract
BACKGROUND: The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered. RESULTS: We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner. CONCLUSION: DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity.
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More information
Published date: 3 February 2006
Additional Information:
Weinkove, David Halstead, Jonathan R Gems, David Divecha, Nullin eng WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England 2006/02/07 BMC Biol. 2006 Feb 3;4:1. doi: 10.1186/1741-7007-4-1.
Keywords:
*Aging Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins/*metabolism Cell Nucleus/metabolism Cytoplasm/*metabolism Dose-Response Relationship, Drug Escherichia coli/metabolism Feedback, Physiological *Food Deprivation Forkhead Transcription Factors Gene Expression Regulation, Developmental Green Fluorescent Proteins/metabolism Hydrogen Peroxide/chemistry/pharmacology Inositol Phosphates/chemistry Mice Models, Biological Mutation Oxidative Stress Phosphatidylinositol 3-Kinases/*metabolism Polymerase Chain Reaction Protein Transport Temperature Time Factors Transcription Factors/*metabolism Transgenes
Identifiers
Local EPrints ID: 479369
URI: http://eprints.soton.ac.uk/id/eprint/479369
ISSN: 1741-7007
PURE UUID: d480b196-7631-4c27-bde7-6465773a0289
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Date deposited: 20 Jul 2023 17:36
Last modified: 17 Mar 2024 03:00
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Author:
D. Weinkove
Author:
J. R. Halstead
Author:
D. Gems
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