Leucine depletion extends the lifespans of leucine-auxotrophic fission yeast by inducing Ecl1 family genes via the transcription factor Fil1
- 212 Downloads
Many studies show that lifespans of various model organisms can be extended by limiting the quantities of nutrients that are necessary for proliferation. In Schizosaccharomyces pombe, the Ecl1 family genes have been associated with lifespan control and are necessary for cell responses to nutrient depletion, but their functions and mechanisms of action remain uncharacterized. Herein, we show that leucine depletion extends the chronological lifespan (CLS) of leucine-auxotrophic cells. Furthermore, depletion of leucine extended CLS and caused cell miniaturization and cell cycle arrest at the G1 phase, and all of these processes depended on Ecl1 family genes. Although depletion of leucine raises the expression of ecl1+ by about 100-fold in leucine-auxotrophic cells, these conditions did not affect ecl1+ expression in leucine-auxotrophic fil1 mutants that were isolated in deletion set screens using 79 mutants disrupting a transcription factor. Fil1 is a GATA-type zinc finger transcription factor that reportedly binds directly to the upstream regions of ecl1+ and ecl2+. Accordingly, we suggest that Ecl1 family genes are induced in response to environmental stresses, such as oxidative stress and heat stress, or by nutritional depletion of nitrogen or sulfur sources or the amino acid leucine. We also propose that these genes play important roles in the maintenance of cell survival until conditions that favor proliferation are restored.
KeywordsEcl1 family gene ecl1+ fil1+ Chronological lifespan Leucine Fission yeast
The authors thank M. Takinami and K. Kanie for helpful discussion, J. Mata for providing permission to use ChIP-sequence data, and M. Yamamoto for the yeast strains. Some S. pombe strains were provided by the National Bio-Resource Project (NBRP) (YGRC) of the MEXT, Japan. The authors would like to thank Enago (www.enago.jp) for the English language review.
This work was supported by the Japan Society for the Promotion of Science KAKENHI Grant Numbers JP16K07662 (to HO), and JP17K19227 and JP17H03792 (to HA). This work was also supported by the Institute for Fermentation, Osaka (to HA).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest with the contents of this article.
- Aris JP, Alvers AL, Ferraiuolo RA, Fishwick LK, Hanvivatpong A, Hu D, Kirlew C, Leonard MT, Losin KJ, Marraffini M, Seo AY, Swanberg V, Westcott JL, Wood MS, Leeuwenburgh C, Dunn WA Jr (2013) Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast. Exp Gerontol 48:1107–1119. https://doi.org/10.1016/j.exger.2013.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
- Duncan CDS, Rodríguez-López M, Ruis P, Bähler J, Mata J (2018) General amino acid control in fission yeast is regulated by a nonconserved transcription factor, with functions analogous to Gcn4/Atf4. Proc Natl Acad Sci USA. 115:E1829–E1838. https://doi.org/10.1073/pnas.1713991115 CrossRefPubMedGoogle Scholar
- Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19:407–417. https://doi.org/10.1016/j.cmet.2014.02.006 CrossRefPubMedPubMedCentralGoogle Scholar
- Murai T, Nakase Y, Fukuda K, Chikashige Y, Tsutsumi C, Hiraoka Y, Matsumoto T (2009) Distinctive responses to nitrogen starvation in the dominant active mutants of the fission yeast Rheb GTPase. Genetics 183:517–527. https://doi.org/10.1534/genetics.109.105379 CrossRefPubMedPubMedCentralGoogle Scholar
- Ohtsuka H, Ogawa S, Kawamura H, Sakai E, Ichinose K, Murakami H, Aiba H (2013) Screening for long-lived genes identifies Oga1, a guanine-quadruplex associated protein that affects the chronological lifespan of the fission yeast Schizosaccharomyces pombe. Mol Genet Genomics 288:285–295. https://doi.org/10.1007/s00438-013-0748-6 CrossRefPubMedGoogle Scholar
- Shimasaki T, Ohtsuka H, Naito C, Azuma K, Tenno T, Hiroaki H, Murakami H, Aiba H (2017) Ecl1 is a zinc-binding protein involved in the zinc-limitation-dependent extension of chronological life span in fission yeast. Mol Genet Genomics 292:475–481. https://doi.org/10.1007/s00438-016-1285-x CrossRefPubMedGoogle Scholar