Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association
Aggregation and Prion-Inducing Properties of the G-Protein Gamma Subunit Ste18 are Regulated by Membrane Association
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DOI：
10.3390/ijms21145038
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发表时间：
2020-07-01
影响因子：
5.6
通讯作者：
Chernoff, Yury O.
中科院分区：
文献类型：
--
作者：
Chernova, Tatiana A.;Yang, Zhen;Chernoff, Yury O.
酵母蛋白和酵母蛋白分别是可传递和不可传递的自我永续蛋白组合，通常基于交叉贝塔有序的抗洗涤剂聚集体(淀粉样蛋白)。Pron在哺乳动物中引起毁灭性的疾病，并控制酵母中的可遗传特征。结果表明，酵母释放因子Sup35的Pron形式[PSI+]的从头形成是由其他蛋白质的聚集体促进的。在这里，我们探索了Ste18促进[PSI+]形成的机制，Ste18是G蛋白偶联受体的一个进化保守的伽玛亚单位，在对细胞外刺激的反应中起着关键作用。Ste18形成耐洗涤剂的聚集体，其中一些与从头生成的Sup35聚集体共存。Ste18的聚集和[PSI+]诱导都需要Ste18的膜结合，而参与信号转导的功能相互作用对这些过程并不是必需的。这强调了特定位置对于蛋白质聚集成核的重要性。与典型的Prion不同，Ste18聚合体没有表现出遗传性的模式。我们的发现是，Ste18的水平受泛素-蛋白酶体系统的调节，再加上之前报道的在交配信息素作用下Ste18水平的增加，表明浓度依赖的Ste18聚集可能介导了对生理刺激的Mnemon样反应。
Yeast prions and mnemons are respectively transmissible and non-transmissible self-perpetuating protein assemblies, frequently based on cross-beta 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.