Identifying Endogenous Cellular Proteins Destabilizing the Propagation of Swi1 Prion upon Overproduction.
Identifying Endogenous Cellular Proteins Destabilizing the Propagation of Swi1 Prion upon Overproduction.
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DOI：
10.3390/v14071366
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发表时间：
2022-06-23
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(1)背景资料：许多朊病毒存在于芽殖酵母中，包括[SWI+]，Swi 1的朊病毒形式-染色质重塑复合物SWI/SNF的亚基。尽管经过几十年的研究，朊病毒启动和繁殖的分子机制尚未完全了解。在这项研究中，我们的目的是确定内源性细胞蛋白不稳定[SWI+]。(2)方法：我们筛选了MoBY-ORF 2.0文库中过量生产时使[SWI+]不稳定的蛋白质。我们进一步探索了所鉴定的候选物对其他酵母朊病毒的影响，并分析了它们潜在的朊病毒治疗机制。(3)结果：共鉴定出82个[SWI+]抑制因子，其作用具有[SWI+]特异性。有趣的是，一些记录的[SWI+]抑制因子不在识别的命中中。进一步的实验表明，对于这些[SWI+]抑制剂中的一些，它们的过量生产，从而它们的朊病毒治疗活性，受到环境条件的调节。生物信息学分析表明，我们确定的[SWI+]抑制因子参与了多种生物学功能，基因本体论术语专门用于转录调控和翻译。[SWI+]和Swi 1相互作用物（包括SWI/SNF复合物）之间对Swi 1单体的竞争是一种潜在的朊病毒治疗机制。(4)结论：我们确定了一些[SWI+]特异性抑制子，这些抑制子突出了[SWI+]在维持其自我永存构象方面的独特功能。
(1) Background: Numerous prions exist in the budding yeast, including [SWI+], the prion form of Swi1—a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this study, we aimed to identify endogenous cellular proteins that destabilize [SWI+]. (2) Methods: We screened the MoBY-ORF 2.0 library for proteins that destabilize [SWI+] upon overproduction. We further explored the effects of the identified candidates against other yeast prions and analyzed their potential prion-curing mechanisms. (3) Results: Eighty-two [SWI+] suppressors were identified, and their effects were shown to be [SWI+]-specific. Interestingly, a few documented [SWI+] suppressors were not among the identified hits. Further experiments indicate that, for some of these [SWI+] suppressors, their overproduction, and thus their prion-curing activities, are regulated by environmental conditions. Bioinformatics analyses show that our identified [SWI+] suppressors are involved in diverse biological functions, with gene ontology term enrichments specifically for transcriptional regulation and translation. Competition for Swi1 monomers between [SWI+] and Swi1 interactors, including the SWI/SNF complex, is a potential prion-curing mechanism. (4) Conclusions: We identified a number of [SWI+]-specific suppressors that highlight unique features of [SWI+] in maintaining its self-perpetuating conformations.
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