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

• 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
• Journal Title: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: Volume 21, Number 14
• Publisher: MDPI AG | 2020-07-16
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3390/ijms21145038
• Subjects: Health Sciences, Oncology; Biology, Cell
• Keywords: prion; amyloid; mnemon; mating; G-protein; Sup35; Ste18; ubiquitin; phosphorylation; yeast

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.