Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling.
The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells. In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.
Lin
K
K
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
Hsin
H
H
Libina
N
N
Kenyon
C
C
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D002467:Cell Nucleus / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D009154:Mutation; D009475:Neurons, Afferent / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D015801:Helminth Proteins; D007328:Insulin; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt