Abstract
Insulin/IGF-1 signaling (IIS) regulates development and metabolism, and modulates aging, of Caenorhabditis elegans. In nematodes, as in mammals, IIS is understood to operate through a kinase-phosphorylation cascade that inactivates the DAF-16/FOXO transcription factor. Situated at the center of this pathway, phosphatidylinositol 3-kinase (PI3K) phosphorylates PIP2 to form PIP3, a phospholipid required for membrane tethering and activation of many signaling molecules. Nonsense mutants of age-1, the nematode gene encoding the class-I catalytic subunit of PI3K, produce only a truncated protein lacking the kinase domain, and yet confer 10-fold greater longevity on second-generation (F2) homozygotes, and comparable gains in stress resistance. Their F1 parents, like weaker age-1 mutants, are far less robust—implying that maternally contributed trace amounts of PI3K activity or of PIP3 block the extreme age-1 phenotypes. We find that F2-mutant adults have <10% of wild-type kinase activity in vitro and <60% of normal phosphoprotein levels in vivo. Inactivation of PI3K not only disrupts PIP3-dependent kinase signaling, but surprisingly also attenuates transcripts of numerous IIS components, even upstream of PI3K, and those of signaling molecules that cross-talk with IIS. The age-1(mg44) nonsense mutation results, in F2 adults, in changes to kinase profiles and to expression levels of multiple transcripts that distinguish this mutant from F1 age-1 homozygotes, a weaker age-1 mutant, or wild-type adults. Most but not all of those changes are reversed by a second mutation to daf-16, implicating both DAF-16/ FOXO–dependent and –independent mechanisms. RNAi, silencing genes that are downregulated in long-lived worms, improves oxidative-stress resistance of wild-type adults. It is therefore plausible that attenuation of those genes in age-1(mg44)-F2 adults contributes to their exceptional survival. IIS in nematodes (and presumably in other species) thus involves transcriptional as well as kinase regulation in a positive-feedback circuit, favoring either survival or reproduction. Hyperlongevity of strong age-1(mg44) mutants may result from their inability to reset this molecular switch to the reproductive mode.
Highlights
IIS depends critically on the presence of PIP3 The IIS pathway, governing developmental arrest, metabolism and life span in Caenorhabditis elegans [1,2,3], is highly conserved from invertebrates to mammals
We discovered the transcriptional arm of this switch in infertile age-1(mg44) mutants, defective for phosphatidylinositol 3-kinase (PI3K) activity
Given the importance of the PIP3 molecule in signal transduction events originating from many membrane-receptor kinases, we anticipated that phosphorylation of numerous proteins may be impaired in those mutants
Summary
IIS depends critically on the presence of PIP3 The IIS pathway, governing developmental arrest, metabolism and life span in Caenorhabditis elegans [1,2,3], is highly conserved from invertebrates to mammals. The single IIS pathway of nematodes corresponds in structure and function to two distinct pathways of mammals that signal metabolic responses to insulin, and growth response to insulin-like growth factor 1 (IGF-1), respectively [4]. IIS disruption was first discovered to enhance longevity in C. elegans [5,6,7,8], but it was subsequently shown to extend life in D. melanogaster and mice [9,10,11]. Binding of insulin-like peptides to DAF-2, the insulin/IGF-1 receptor of nematodes, modulates receptor autophosphorylation and activation [12]. Activated AGE-1 adds a phosphate to phosphatidylinositol 4,5-diphosphate [PI(4,5)P2] at the inositolring 3-position, converting it to phosphatidylinositol 3,4,5triphosphate [PI(3,4,5)P3 or PIP3]
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