title: DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans.
abstract: The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved.
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Jennifer M A
authors: JM
authors: Tullet
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Caroline
authors: C
authors: Araiz
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Matthew J
authors: MJ
authors: Sanders
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Catherine
authors: C
authors: Au
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Alexandre
authors: A
authors: Benedetto
authors: EMBL, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Irene
authors: I
authors: Papatheodorou
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Emily
authors: E
authors: Clark
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Kathrin
authors: K
authors: Schmeisser
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Daniel
authors: D
authors: Jones
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: Eugene F
authors: EF
authors: Schuster
authors: EMBL, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors: Janet M
authors: JM
authors: Thornton
authors: Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
authors: David
authors: D
authors: Gems
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D020033:Protein Isoforms; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; D055372:AMP-Activated Protein Kinases