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Abstract
In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs 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.
Highlights
Cell size and proliferation are fundamental determinants of development, survival, and disease (Su and O’Farrell, 1998)
We recently discovered more than 40 protein-based epigenetic elements in Saccharomyces cerevisiae that are both heritable and reversible upon transient perturbation of protein chaperone function (Chakrabortee et al, 2016a)
Many of the proteins that underlie this behavior have the potential to regulate growth. One of these epigenetic states was induced by transient overexpression of the highly conserved pseudouridine synthase PUS4/TRUB, which catalyzes the formation of a ubiquitous pseudouridine on U55 in tRNAs in bacteria, yeast, and humans (Becker et al, 1997; Gutgsell et al, 2000; Zucchini et al, 2003)
Summary
Cell size and proliferation are fundamental determinants of development, survival, and disease (Su and O’Farrell, 1998). They can be independently controlled—for example, when cell division is disrupted, cell size continues to increase, whereas restricting cell growth does not completely inhibit division (Johnston et al, 1977)—coupling is common due to their dependence on the same biochemical building blocks (Su and O’Farrell, 1998; Turner et al, 2012).
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