Abstract
Tight coupling of cell growth and cell cycle progression enable cells to adjust their rate of division, and therefore size, to the demands of proliferation in varying nutritional environments. Nutrient stress promotes inhibition of Target Of Rapamycin Complex 1 (TORC1) activity. In fission yeast, reduced TORC1 activity advances mitotic onset and switches growth to a sustained proliferation at reduced cell size. A screen for mutants, that failed to advance mitosis upon nitrogen stress, identified a mutant in the PIKFYVE 1-phosphatidylinositol-3-phosphate 5-kinase fission yeast homolog Ste12. Ste12PIKFYVE deficient mutants were unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline) growth conditions. While it is well established that PI(3,5)P2 signalling is required for autophagy and that Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes), neither a block to autophagy or mutants that independently have enlarged vacuoles had any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE deficient mutants reduced cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. ste12 mutants display increased Torin1 (TOR inhibitor) sensitivity. However, no major impact on TORC1 or TORC2 activity was observed in the ste12 deficient mutants. In summary, Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division.
Highlights
In the presence of rich nutrients, cells maintain high levels of macromolecular synthesis to promote growth and increase size
A number of studies have focused on identifying and characterising upstream regulators of Target Of Rapamycin Complex 1 (TORC1) that respond to amino acid or glucose availability [10, 11], little is known about how cells sense nitrogen quality, and how this signal is relayed to TORC1 to adjust cell size
Nitrogen stress alters the timing of mitotic commitment in fission yeast, such that a reduction in nitrogen quality accelerates mitotic commitment, leading to a concomitant reduction in cell size at division (Fantes and Nurse, 1977)
Summary
In the presence of rich nutrients, cells maintain high levels of macromolecular synthesis to promote growth and increase size. Inhibition of TOR signalling with rapamycin, a TORC1 inhibitor, mimics the impact of nutrient stress to reduce cell size, both in S. pombe [6] and mammalian cells [9]. A number of studies have focused on identifying and characterising upstream regulators of TORC1 that respond to amino acid or glucose availability [10, 11], little is known about how cells sense nitrogen quality, and how this signal is relayed to TORC1 to adjust cell size . We report a novel function for the fission yeast PIKFYVE kinase Ste12PIKFYVE, in the regulation of mitotic commitment. A genetic screen identified a non-functional ste12PIKFYVE mutant that was unable to invoke the normal advancement of mitotic onset and adjust cell size at division in response to nitrogen stress
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