A prion accelerates proliferation at the expense of lifespan [samples with spike-in controls]

Manuscript abstract: In fluctuating environments, the ability to switch between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Tradeoffs arise, however. Mechanisms that aberrantly increase cell size or proliferation— such as mutations, or chemicals that interfere with growth regulatory pathways—can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.