Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm
Tóm tắt
The provision of stress resistance diverts resources from development and reproduction and must therefore be tightly regulated. In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm. However, the circumstances under which AGE-1 is normally activated are unclear. To address this question we used C. elegans first stage larvae (L1s), which when starved enter a developmentally-arrested diapause stage until food is encountered. We find that in L1s both starvation and daf-16 are necessary to confer resistance to oxidative stress in the form of hydrogen peroxide. Accordingly, DAF-16 is localised to cell nuclei after short-term starvation. However, after long-term starvation, DAF-16 unexpectedly translocates to the cytoplasm. This translocation requires functional age-1. H2O2 treatment can replicate the translocation and induce generation of the AGE-1 product PIP3. Because feeding reduces to zero in ageing adult C. elegans, these animals may also undergo long-term starvation. Consistent with our observation in L1s, DAF-16 also translocates to the cytoplasm in old adult worms in an age-1-dependent manner. DAF-16 is activated in the starved L1 diapause. The translocation of DAF-16 to the cytoplasm after long-term starvation may be a feedback mechanism that prevents excessive expenditure on stress resistance. H2O2 is a candidate second messenger in this feedback mechanism. The lack of this response in age-1(hx546) mutants suggests a novel mechanism by which this mutation increases longevity.
Tài liệu tham khảo
Kirkwood TB: Understanding the odd science of aging. Cell. 2005, 120 (4): 437-447. 10.1016/j.cell.2005.01.027.
Riddle DL, Swanson MM, Albert PS: Interacting genes in nematode dauer larva formation. Nature. 1981, 290 (5808): 668-671. 10.1038/290668a0.
Klass M, Hirsh D: Non-ageing developmental variant of Caenorhabditis elegans. Nature. 1976, 260 (5551): 523-525. 10.1038/260523a0.
Henderson ST, Johnson TE: daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001, 11 (24): 1975-1980. 10.1016/S0960-9822(01)00594-2.
Friedman DB, Johnson TE: A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988, 118 (1): 75-86.
Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R: A C. elegans mutant that lives twice as long as wild type. Nature. 1993, 366 (6454): 461-464. 10.1038/366461a0.
McElwee J, Bubb K, Thomas JH: Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell. 2003, 2 (2): 111-121. 10.1046/j.1474-9728.2003.00043.x.
McElwee JJ, Schuster E, Blanc E, Thomas JH, Gems D: Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem. 2004, 279 (43): 44533-44543. 10.1074/jbc.M406207200.
Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C: Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003, 424 (6946): 277-283. 10.1038/nature01789.
Gems D, Sutton AJ, Sundermeyer ML, Albert PS, King KV, Edgley ML, Larsen PL, Riddle DL: Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics. 1998, 150: 129-155.
Jenkins NL, McColl G, Lithgow GJ: Fitness cost of extended lifespan in Caenorhabditis elegans. Proc Biol Sci. 2004, 271 (1556): 2523-2526. 10.1098/rspb.2004.2897.
Lee RY, Hench J, Ruvkun G: Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol. 2001, 11 (24): 1950-1957. 10.1016/S0960-9822(01)00595-4.
Lin K, Hsin H, Libina N, Kenyon C: Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001, 28 (2): 139-145. 10.1038/88850.
Walker DW, McColl G, Jenkins NL, Harris J, Lithgow GJ: Evolution of lifespan in C. elegans. Nature. 2000, 405 (6784): 296-297. 10.1038/35012693.
Johnson TE, Henderson S, Murakami S, de Castro E, de Castro SH, Cypser J, Rikke B, Tedesco P, Link C: Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J Inherit Metab Dis. 2002, 25 (3): 197-206. 10.1023/A:1015677828407.
Morris JZ, Tissenbaum HA, Ruvkun G: A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996, 382 (6591): 536-539. 10.1038/382536a0.
Larsen PL: Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1993, 90 (19): 8905-8909.
Vanfleteren JR: Oxidative stress and ageing in Caenorhabditis elegans. Biochem J. 1993, 292 (Pt 2): 605-608.
Johnson TE, Mitchell DH, Kline S, Kemal R, Foy J: Arresting development arrests aging in the nematode Caenorhabditis elegans. Mech Ageing Dev. 1984, 28 (1): 23-40. 10.1016/0047-6374(84)90150-7.
Honda Y, Honda S: The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. Faseb J. 1999, 13 (11): 1385-1393.
Murakami S, Johnson TE: A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics. 1996, 143 (3): 1207-1218.
Paradis S, Ruvkun G: Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 1998, 12 (16): 2488-2498.
Ogg S, Ruvkun G: The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell. 1998, 2 (6): 887-893. 10.1016/S1097-2765(00)80303-2.
Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA: JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A. 2005, 102 (12): 4494-4499. 10.1073/pnas.0500749102.
Schwarzer R, Dames S, Tondera D, Klippel A, Kaufmann J: TRB3 is a PI 3-kinase dependent indicator for nutrient starvation. Cell Signal. 2005
Harrington LS, Findlay GM, Lamb RF: Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci. 2005, 30 (1): 35-42. 10.1016/j.tibs.2004.11.003.
Nemoto S, Finkel T: Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science. 2002, 295 (5564): 2450-2452. 10.1126/science.1069004.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM: Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002, 419 (6904): 316-321. 10.1038/nature01036.
Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG: Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002, 277 (23): 20336-20342. 10.1074/jbc.M111899200.
Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP: Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 2003, 22 (20): 5501-5510. 10.1093/emboj/cdg513.
Deora AA, Win T, Vanhaesebroeck B, Lander HM: A redox-triggered ras-effector interaction. Recruitment of phosphatidylinositol 3'-kinase to Ras by redox stress. J Biol Chem. 1998, 273 (45): 29923-29928. 10.1074/jbc.273.45.29923.
Halstead JR, Roefs M, Ellson CD, D'Andrea S, Chen C, D'Santos CS, Divecha N: A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress. Curr Biol. 2001, 11 (6): 386-395. 10.1016/S0960-9822(01)00121-X.
Puig O, Marr MT, Ruhf ML, Tjian R: Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 2003, 17 (16): 2006-2020. 10.1101/gad.1098703.
Huang C, Xiong C, Kornfeld K: Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2004, 101 (21): 8084-8089. 10.1073/pnas.0400848101.
Henderson ST, Johnson TE: daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Current Biology. 2005, 15 (7): 690-10.1016/j.cub.2005.03.045.
Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG: The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999, 402 (6759): 309-313. 10.1038/46311.
Wicks SR, Yeh RT, Gish WR, Waterston RH, Plasterk RH: Rapid gene mapping in Caenorhabditis elegans using a high density polymorphism map. Nat Genet. 2001, 28 (2): 160-164. 10.1038/88878.