A new DAF-16 isoform regulates longevity.
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
Kwon
Eun-Soo
ES
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Narasimhan
Sri Devi
SD
Yen
Kelvin
K
Tissenbaum
Heidi A
HA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
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; C525107:Sod-3 protein, C elegans; D013482:Superoxide Dismutase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C494915:akt-1 protein, C elegans; C494916:akt-2 protein, C elegans