Title: The Target of Rapamycin Pathway Antagonizes pha-4/FoxA to Control Development and Aging
Abstract: BackgroundFoxA factors are critical regulators of embryonic development and postembryonic life, but little is know about the upstream pathways that modulate their activity [1Friedman J.R. Kaestner K.H. The Foxa family of transcription factors in development and metabolism.Cell. Mol. Life Sci. 2006; 63: 2317-2328Crossref PubMed Scopus (343) Google Scholar]. C. elegans pha-4 encodes a FoxA transcription factor that is required to establish the foregut in embryos and to control growth and longevity after birth [2Mango, S.E. (2007). The C. elegans pharynx: A model for organogenesis. In WormBook, The C. elegans Research Community, ed. 10.1895/wormbook.1.129.1, http://www.wormbook.org.Google Scholar, 3Panowski S.H. Wolff S. Aguilaniu H. Durieux J. Dillin A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans.Nature. 2007; 447: 550-555Crossref PubMed Scopus (391) Google Scholar, 4Ao W. Gaudet J. Kent W.J. Muttumu S. Mango S.E. Environmentally induced foregut remodeling by PHA-4/FoxA and DAF-12/NHR.Science. 2004; 305: 1743-1746Crossref PubMed Scopus (143) Google Scholar, 5Gaudet J. Mango S.E. Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4.Science. 2002; 295: 821-825Crossref PubMed Scopus (287) Google Scholar]. We previously identified the AAA+ ATPase homolog ruvb-1 as a potent suppressor of pha-4 mutations [6Updike D.L. Mango S.E. Genetic suppressors of Caenorhabditis elegans pha-4/FoxA identify the predicted AAA helicase ruvb-1/RuvB.Genetics. 2007; 177: 819-833Crossref PubMed Scopus (13) Google Scholar].ResultsHere we show that ruvb-1 is a component of the Target of Rapamycin (TOR) pathway in C. elegans (CeTOR). Both ruvb-1 and let-363/TOR control nucleolar size and promote localization of box C/D snoRNPs to nucleoli, suggesting a role in rRNA maturation. Inactivation of let-363/TOR or ruvb-1 suppresses the lethality associated with reduced pha-4 activity. The CeTOR pathway controls protein homeostasis and also contributes to adult longevity [7Kaeberlein M. Kennedy B.K. Protein translation, 2007.Aging Cell. 2007; 6: 731-734Crossref PubMed Scopus (39) Google Scholar, 8Vellai T. Takacs-Vellai K. Zhang Y. Kovacs A.L. Orosz L. Muller F. Genetics: Influence of TOR kinase on lifespan in C. elegans.Nature. 2003; 426: 620Crossref PubMed Scopus (767) Google Scholar]. We find that pha-4 is required to extend adult lifespan in response to reduced CeTOR signaling. Mutations in the predicted CeTOR target rsks-1/S6 kinase or in ife-2/eIF4E also reduce protein biosynthesis and extend lifespan [9Hansen M. Taubert S. Crawford D. Libina N. Lee S.J. Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans.Aging Cell. 2007; 6: 95-110Crossref PubMed Scopus (578) Google Scholar, 10Pan K.Z. Palter J.E. Rogers A.N. Olsen A. Chen D. Lithgow G.J. Kapahi P. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans.Aging Cell. 2007; 6: 111-119Crossref PubMed Scopus (352) Google Scholar, 11Syntichaki P. Troulinaki K. Tavernarakis N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans.Nature. 2007; 445: 922-926Crossref PubMed Scopus (249) Google Scholar], but only rsks-1 mutations require pha-4 for adult longevity. In addition, rsks-1, but not ife-2, can suppress the larval lethality associated with pha-4 loss-of-function mutations.ConclusionsThe data suggest that pha-4 and the CeTOR pathway antagonize one another to regulate postembryonic development and adult longevity. We suggest a model in which nutrients promote TOR and S6 kinase signaling, which represses pha-4/FoxA, leading to a shorter lifespan. A similar regulatory hierarchy may function in other animals to modulate metabolism, longevity, or disease.