A prion accelerates proliferation at the expense of lifespan

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.

Biochemical Principles in Prion-Based Inheritance

“…Curing of amyloid-forming prions can be accomplished through transient inhibition of the protein disaggregase chaperone, Hsp104. In contrast, the non-amyloid-forming prions can be cured by transient Hsp70 inhibition, but not Hsp104 inhibition [ 4 , 5 , 7 ]. IDRs are another feature of non-amyloid-forming prions that have been identified as drivers of prion phenotypes [ 7 ] (as noted earlier, these may also be found in amyloid-forming prions).…”

“…For example, the IDR region in the [ SMAUG + ] prion drives its self-assembly properties, allowing gel-like condensates to form [ 23 ]. It is possible that the more dynamic structure of non-amyloid assemblies allows manipulation of phenotypic states without elimination of protein activity [ 5 , 7 , 23 , 24 ], permitting a regulatory paradigm of prion induction and loss in response to environmental cues. More characterization is needed before such conclusions can be established.…”

“…GFP-fusion proteins allow visualization of prion aggregation in vivo, a useful tool for observing protein localization, aggregation formation, and induction of the prion state [ 78 ]. This has been used in characterizing [ PSI + ], [ MOT3 + ], [ BIG + ], [ SMAUG + ] and more [ 3 , 5 , 23 , 79 ]. Fluorescent-reporter systems have also been developed for studying the kinetics of prion assembly formation, such as DAmFRET [ 80 ] and yTRAP [ 81 ], using [ PSI + ] to demonstrate their effectiveness.…”

“…Today, our understanding of prion proteins is significantly more expansive—in rare cases they can cause disease, but there are even more examples of how they can be beneficial to organisms, permitting adaptation to environmental change [ 3 ], altered metabolism [ 4 ], increased cellular growth [ 5 ], and resistance to chemical stressors [ 6 ]. Prions also fundamentally alter our view of inheritance, as their ability to phenotypically alter an organism is based on heritable differences in protein structure and not any change to DNA sequence.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…The symptom of prion protein infection was first described in 1732 when Merino sheep scraped pathologically against fences [ 1 ], but the term prion (PRoteinaceous Infective ONly particle) was not coined until 1982 by Prusiner who defined prions in 1998 as heritable, infectious, proteinaceous particles that are converted from the normal, cellular form (PrP C ) into the pathogenic form (PrP Sc ) that associates with amyloid plaques [ 2 , 3 ]. The full-length prion protein (PrP) [ 4 ] exists as a native, soluble cellular PrP C isoform with important physiological functions [ 5 ] including cellular differentiation [ 6 , 7 , 8 ], proliferation [ 9 ], and adhesion [ 10 ]; myelin maintenance [ 11 ]; circadian rhythm regulation [ 12 , 13 ]; signal transduction [ 14 ]; glucose homeostasis [ 15 , 16 ]; immune regulation [ 17 , 18 ]; as well as copper homeostasis, utilization [ 19 , 20 ]; iron uptake, transport, and metabolism [ 21 , 22 , 23 ]; and even facilitating the persistence and storage of memory [ 24 , 25 ]. In humans, quantitative transcriptomics analysis (RNA-Seq) of 27 different tissues obtained from 95 human individuals [ 26 ] found the prion gene PRNP to be ubiquitously expressed in all 27 human tissues examined in addition to mitochondria, with the highest expressions found in the brain, followed by the ovary, prostate, heart, gallbladder, endometrium, adrenal, urinary bladder, thyroid, testis, skin, esophagus, and lung [ 27 ].…”