Abstract
SummaryTarget of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not.
Highlights
Lifespan is not invariably fixed but determined by genetic and environmental factors that are remarkably conserved across organisms
The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study Target of rapamycin complex 1 (TORC1) function and cellular ageing
We exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner
Summary
Lifespan is not invariably fixed but determined by genetic and environmental factors that are remarkably conserved across organisms. Budding yeast (Saccharomyces cerevisiae) has a long track record in providing fundamental insight into molecular mechanisms of cellular ageing (Kaeberlein, 2010). The conserved nutrient-responsive target of rapamycin (TOR) pathway regulates growth, metabolism and lifespan (Laplante and Sabatini, 2012; Wullschleger et al, 2006). TOR proteins are serine/threonine kinases found in two complexes: TORC1 and TORC2 (Wullschleger et al, 2006). TORC1 signaling promotes protein synthesis and ageing, and regulates growth in response to nitrogen or amino acid availability (Matsuo et al, 2007; Weisman, 2010). TORC1 promotes protein translation by phosphorylation of ribosomal S6 kinases and the eIF4E-binding protein (Laplante and Sabatini, 2012)
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