Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins.

IF 3.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Dustin Goncharoff, Zhiqiang Du, Shriram Venkatesan, Brandon Cho, Jenny Zhao, Milad J Alasady, Dalton Huey, Hannah Ma, Jake Rosenthal, Alexander Turenitsa, Coral Feldman, Randal Halfmann, Marc L Mendillo, Liming Li
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Abstract

Cancer encompasses a range of severe diseases characterized by uncontrolled cell growth and the potential for metastasis. Understanding the mechanism underlying tumorigenesis has been a central focus of cancer research. Self-propagating protein aggregates, known as prions, are linked to various biological functions and diseases, particularly those related to mammalian neurodegeneration. However, it remains unclear whether prion-like mechanisms contribute to tumorigenesis and cancer. Using a combined approach of algorithmic predictions, alongside genetic and biochemical experimentation, we identified numerous cancer-associated proteins prone to aggregation, many of which contain prion-like domains (PrLDs). These predictions were experimentally validated for both aggregation and prion-formation. We demonstrate that several PrLDs undergo nucleation-limited amyloid formation, which can alter protein activity in a mitotically heritable fashion. These include SSXT, a subunit of the chromatin-remodeling BAF (hSWI/SNF) complexes; CLOCK, a core component of the circadian clock; and EPN4, a clathrin-interacting protein involved in protein trafficking between the trans-Golgi network and endosomes. The prions formed by these PrLDs occurred in multiple variants and depended on Hsp104, a molecular chaperone with disaggregase activity. Our results reveal an inherent tendency for prion-like aggregation in human cancer-associated proteins, suggesting a potential role for such aggregation in the epigenetic changes driving tumorigenesis.

研究人类癌症相关蛋白的聚集和致朊特性。
癌症包括一系列以不受控制的细胞生长和潜在的转移为特征的严重疾病。了解肿瘤发生的机制一直是癌症研究的中心焦点。被称为朊病毒的自我繁殖的蛋白质聚集体与各种生物功能和疾病有关,特别是与哺乳动物神经变性有关的疾病。然而,目前尚不清楚朊病毒样机制是否有助于肿瘤发生和癌症。使用算法预测的结合方法,以及遗传和生化实验,我们确定了许多易于聚集的癌症相关蛋白,其中许多含有朊病毒样结构域(prld)。这些预测在聚集和朊病毒形成方面都得到了实验验证。我们证明了几个prld经历核限制淀粉样蛋白形成,这可以以有丝分裂遗传的方式改变蛋白质活性。这些包括SSXT,染色质重塑BAF (hSWI/SNF)复合物的一个亚基;时钟,生物钟的核心组成部分;EPN4是一种网格蛋白相互作用蛋白,参与反式高尔基网络和核内体之间的蛋白质运输。这些prld形成的朊病毒有多种变体,依赖于具有分解酶活性的分子伴侣Hsp104。我们的研究结果揭示了人类癌症相关蛋白中朊病毒样聚集的固有趋势,表明这种聚集在驱动肿瘤发生的表观遗传变化中具有潜在作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular and Cellular Biology
Molecular and Cellular Biology 生物-生化与分子生物学
CiteScore
9.80
自引率
1.90%
发文量
120
审稿时长
1 months
期刊介绍: Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.
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