Phase Separation of Epstein-Barr Virus EBNA2 and Its Coactivator EBNALP Controls Gene Expression
Phase Separation of Epstein-Barr Virus EBNA2 and Its Coactivator EBNALP Controls Gene Expression
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Epstein-Barr 病毒 EBNA2 及其辅激活剂 EBNALP 的相分离控制基因表达
DOI：
10.1128/jvi.01771-19
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发表时间：
2020-04-01
影响因子：
5.4
通讯作者：
Ma, Jian
中科院分区：
文献类型：
--
作者：
Peng, Qiu;Wang, Lujuan;Ma, Jian
蛋白质凝聚体可以通过液-液相分离（LLPS）来组装，这是一种在受限的液体状隔间中进行分子浓缩的过程。LLPS允许隔离和隔离材料，可以作为一种敏感的策略来应对环境中的微小变化。本研究发现介导病毒和细胞基因转录的eb病毒（EBV）蛋白EBNA2和EBNALP是转录因子，可在MYC和Runx3的超增强位点形成液体状凝聚体。本研究首次发现了EBV蛋白的LLPS，强调了LLPS在控制宿主基因表达中的重要性。近年来，人们发现液-液相分离形成的生物大分子凝聚物（LLPS）在生物学中普遍存在。这些凝聚物参与多种过程，包括基因表达的调节。蛋白的LLPS已在动物、植物和细菌物种中发现，但在病毒蛋白中几乎没有发现。在这里，我们发现eb病毒（EBV） EBNA2和ebnap形成核点，表现出液体状凝聚物（或液滴）的特性，这些核点富含MYC和Runx3的超增强剂。EBNA2和EBNALP是转录因子，它们的靶基因的表达受到干扰LLPS的化学物质的抑制。EBNA2和EBNALP的内在无序区（IDRs）可以形成相分离的液滴，EBNA2和EBNALP的特定脯氨酸残基有助于液滴的形成。这些发现为理解LLPS的机制提供了基础，LLPS先前被认为与P体的组织、无膜细胞器、核核稳态和细胞信号传导有关，在ebv -宿主相互作用中起关键作用，并参与调节宿主基因表达。这项工作提出了一种新的抗EBV策略，即开发适当的干扰LLPS药物可以用来破坏EBV转录因子的功能。蛋白质凝聚物可以通过液-液相分离（LLPS）来组装，这是一种在受限的液体样隔间中进行分子浓缩的过程。LLPS允许隔离和隔离材料，可以作为一种敏感的策略来应对环境中的微小变化。本研究发现介导病毒和细胞基因转录的eb病毒（EBV）蛋白EBNA2和EBNALP是转录因子，可在MYC和Runx3的超增强位点形成液体状凝聚体。本研究首次发现了EBV蛋白的LLPS，强调了LLPS在控制宿主基因表达中的重要性。
Protein condensates can be assembled via liquid-liquid phase separation (LLPS), a process involving the concentration of molecules in a confined liquid-like compartment. LLPS allows for the compartmentalization and sequestration of materials and can be harnessed as a sensitive strategy for responding to small changes in the environment. This study identified the Epstein-Barr virus (EBV) proteins EBNA2 and EBNALP, which mediate virus and cellular gene transcription, as transcription factors that can form liquid-like condensates at superenhancer sites of MYC and Runx3. This study discovered the first identified LLPS of EBV proteins and emphasized the importance of LLPS in controlling host gene expression. ABSTRACT Biological macromolecule condensates formed by liquid-liquid phase separation (LLPS) have been discovered in recent years to be prevalent in biology. These condensates are involved in diverse processes, including the regulation of gene expression. LLPS of proteins have been found in animal, plant, and bacterial species but have scarcely been identified in viral proteins. Here, we discovered that Epstein-Barr virus (EBV) EBNA2 and EBNALP form nuclear puncta that exhibit properties of liquid-like condensates (or droplets), which are enriched in superenhancers of MYC and Runx3. EBNA2 and EBNALP are transcription factors, and the expression of their target genes is suppressed by chemicals that perturb LLPS. Intrinsically disordered regions (IDRs) of EBNA2 and EBNALP can form phase-separated droplets, and specific proline residues of EBNA2 and EBNALP contribute to droplet formation. These findings offer a foundation for understanding the mechanism by which LLPS, previously determined to be related to the organization of P bodies, membraneless organelles, nucleolus homeostasis, and cell signaling, plays a key role in EBV-host interactions and is involved in regulating host gene expression. This work suggests a novel anti-EBV strategy where developing appropriate drugs of interfering LLPS can be used to destroy the function of the EBV’s transcription factors. IMPORTANCE Protein condensates can be assembled via liquid-liquid phase separation (LLPS), a process involving the concentration of molecules in a confined liquid-like compartment. LLPS allows for the compartmentalization and sequestration of materials and can be harnessed as a sensitive strategy for responding to small changes in the environment. This study identified the Epstein-Barr virus (EBV) proteins EBNA2 and EBNALP, which mediate virus and cellular gene transcription, as transcription factors that can form liquid-like condensates at superenhancer sites of MYC and Runx3. This study discovered the first identified LLPS of EBV proteins and emphasized the importance of LLPS in controlling host gene expression.