Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association

• Type of Material: Article
• Authors: Tatiana Chernova, Emory University; Zhen Yang, Emory University; Tatiana S. Karpova, National Cancer Institute; John R. Shanks, Emory University; Natalia Shcherbik, Rowan University; Keith Wilkinson, Emory University; Yury O. Chernoff, Georgia Institute of Technology
• Language: English
• Date: 2020-07-16
• Publisher: MDPI AG
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms21145038
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 21
• Issue: 14
• Grant/Funding Information: This research was funded by the grants MCB 1817976 (to Y.O.C.) from the National Science Foundation, R01GM114308 (to N.S.) and R01GM093294 (to K.D.W.) from the National Institutes of Health, and by the Intramural Research Program of the National Institutes of Health (to T.S.K.).
• Keywords: mnemon; phosphorylation; yeast; mating; amyloid; G-protein; prion; ubiquitin; Ste18; Sup35
• Research Categories: Biology, Cell; Health Sciences, Oncology

Abstract

Yeast prions and mnemons are respectively transmissible and non-transmissible self-perpetuating protein assemblies, frequently based on cross-β ordered detergent-resistant aggregates (amyloids). Prions cause devastating diseases in mammals and control heritable traits in yeast. It was shown that the de novo formation of the prion form [PSI+] of yeast release factor Sup35 is facilitated by aggregates of other proteins. Here we explore the mechanism of the promotion of [PSI+] formation by Ste18, an evolutionarily conserved gamma subunit of a G-protein coupled receptor, a key player in responses to extracellular stimuli. Ste18 forms detergent-resistant aggregates, some of which are colocalized with de novo generated Sup35 aggregates. Membrane association of Ste18 is required for both Ste18 aggregation and [PSI+] induction, while functional interactions involved in signal transduction are not essential for these processes. This emphasizes the significance of a specific location for the nucleation of protein aggregation. In contrast to typical prions, Ste18 aggregates do not show a pattern of heritability. Our finding that Ste18 levels are regulated by the ubiquitin-proteasome system, in conjunction with the previously reported increase in Ste18 levels upon the exposure to mating pheromone, suggests that the concentration-dependent Ste18 aggregation may mediate a mnemon-like response to physiological stimuli.