Skip to main content
Kent Academic Repository

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

Tullet, Jennifer M.A., Araiz, Caroline, Sanders, Matthew J, Au, Catherine, Benedetto, Alexandre, Papatheodorou, Irene, Clark, Emily, Schmeisser, Kathrin, Jones, Daniel, Schuster, Eugene F, and others. (2014) 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. PLoS genetics, 10 (2). Article Number 1004109. ISSN 1553-7404. (doi:10.1371/journal.pgen.1004109) (KAR id:43254)

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 ?, ? and ? subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory ? 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 ? 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 ? 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 ? 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.

Item Type: Article
DOI/Identification number: 10.1371/journal.pgen.1004109
Subjects: Q Science > Q Science (General)
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Jennifer Tullet
Date Deposited: 13 Oct 2014 08:25 UTC
Last Modified: 05 Nov 2024 10:27 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/43254 (The current URI for this page, for reference purposes)

University of Kent Author Information

Tullet, Jennifer M.A..

Creator's ORCID: https://orcid.org/0000-0002-2037-526X
CReDIT Contributor Roles:
  • Depositors only (login required):

Total unique views for this document in KAR since July 2020. For more details click on the image.