Rapamycin-sensitive mechanisms confine the growth of fission yeast below the temperatures detrimental to cell physiology

Abstract

AbstractCells cease to proliferate above their growth-permissible temperatures, a ubiquitous phenomenon generally attributed to protein denaturing and heat damage to other cellular macromolecules. We here report that, in the presence of the macrolide compound rapamycin, the fission yeastSchizosaccharomyces pombecan proliferate at high temperatures that normally arrest its growth. Rapamycin is a potent inhibitor of the protein kinase complex TOR Complex 1 (TORC1), and consistently, mutations to the TORC1 subunit RAPTOR/Mip1 and the TORC1 substrate Sck1 significantly improve cellular heat resistance. These results suggest that TORC1, a well-established growth promoter, restricts the high-temperature growth of fission yeast and that compromised TORC1 signaling allows cell proliferation at higher temperatures. Aiming for a more comprehensive understanding of the negative regulation of high-temperature growth, we conducted genome-wide screens inS. pombe, which identified Sck1 and additional factors that appear to suppress cell proliferation at high temperatures. Our study has uncovered unexpected mechanisms of growth restraint even below the temperatures deleterious to cell physiology. Thus, growth arrest at high temperatures may not directly result from heat damage to cellular components essential for proliferation and viability.Significance StatementThe immunosuppressant rapamycin is a specific inhibitor of the protein kinase Target Of Rapamycin (TOR), and the drug is known to extend the lifespan of diverse eukaryotic organisms. In this study, we have found that rapamycin confers heat resistance on fission yeast, allowing its proliferation above the normal permissive temperatures. This unexpected observation suggests that TOR, which is known as a growth-promoting kinase, is inhibitory to cell proliferation at high temperatures. Our genome-wide screens have identified additional genes whose deletion leads to improved growth under heat stress. Thus, cells may have mechanisms that restrict proliferation even below the temperatures deleterious to their physiology.