Cellular functions of hub proteins and their deregulation by adenovirus

枢纽蛋白的细胞功能及其腺病毒对其的失调

• 批准号: RGPIN-2019-05366
• 负责人: Pelka, Peter
• 金额: $ 2.33万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=715519
• 关键词: Cellular; functions; hub; proteins; their

Cellular regulatory networks are inherently redundant, representing a multi-node scale-free network that is resistant to disruptions. This type of organization is necessary to avoid critical network failure upon disruption of a single node. The inherent weakness of a cellular regulatory network lies in key regulators of network function, known as "hub proteins". Viruses have evolved exquisite ways in which to target these hubs in order to remodel the network and enable virus propagation and host evasion. Therefore, utilization of viral proteins that remodel the cell provides a useful means of identifying key cellular regulators of important processes. I have identified two novel cellular regulators by their virtue of binding to the adenovirus immediate early gene product E1A: DREF and FUBP1. Both of these proteins are poorly understood and their function within cells is enigmatic. DREF is a transcriptional regulator that is involved in activation of cell cycle and growth control genes. FUBP1 is a protein that appears to play a role in transcriptional regulation by binding to enhancers within gene regulatory regions as well as regulating protein translation. The E1A protein of adenovirus is a small protein composed of 289 amino acids in the largest isoform. E1A can be considered a "hub detector" because of its ability to target key cellular regulators. E1A has been an invaluable tool in the study and understanding of a wide variety of cellular processes. Recent NSERC--funded studies in my laboratory have begun to unravel the mysteries of cellular hub proteins. We have discovered new functions of DREF and FUBP1, in large part thanks to my use of E1A as a molecular probe for dissection of cellular pathways. Work in my lab has identified, for the first time, that DREF is a component of cellular innate immune response and it is deregulated by alteration of its SUMOylation by E1A during virus-driven cellular reprogramming. My lab has also shown that FUBP1 is utilized by E1A to suppress cellular stress response pathway by locking FUBP1 in a complex with the cellular stress regulator p53, preventing p53 from carrying out its functions. These studies only scratch the surface of what the pathways and functions are of DREF and FUBP1, paving the way for further investigations. Study of E1A--binding proteins teaches us not only about E1A but also about the proteins that bind to it. Importantly, discovery of novel E1A-binding proteins identifies key cellular hubs that can be studied using this powerful viral tool. My research program focuses on the identification and characterizaton of cellular hub proteins to better understand their role in cellular processes governing eukaryotic life. In the short term, studies of DREF and FUBP1, and their association with E1A, will clarify their cellular functions and elucidate the reasons behind their targeting by a virus.

细胞调控网络具有内在冗余性，代表了一个多节点的无标度网络，可以抵抗中断。这种类型的组织是必要的，以避免在单个节点中断时发生关键网络故障。细胞调控网络的固有弱点在于网络功能的关键调控因子，称为“枢纽蛋白”。病毒已经进化出了针对这些集线器的精致方式，以重塑网络并实现病毒传播和主机逃避。因此，利用病毒蛋白重塑细胞提供了一个有用的手段，确定重要的过程中的关键细胞调节。通过与腺病毒立即早期基因产物E1A的结合，我鉴定了两种新的细胞调节因子：DREF和FUBP 1。这两种蛋白质都知之甚少，它们在细胞内的功能也是个谜。DREF是一种转录调节因子，参与细胞周期和生长控制基因的激活。FUBP 1是一种蛋白质，其似乎通过与基因调控区内的增强子结合以及调节蛋白质翻译而在转录调控中发挥作用。 腺病毒的E1A蛋白是由289个氨基酸组成的最大同种型的小蛋白。E1A可以被认为是一个“枢纽检测器”，因为它能够靶向关键的细胞调节因子。E1A是研究和理解各种细胞过程的宝贵工具。 最近在我的实验室里，NSERC资助的研究已经开始揭开细胞中心蛋白的奥秘。我们已经发现了DREF和FUBP 1的新功能，这在很大程度上要归功于我使用E1A作为分子探针来解剖细胞通路。我实验室的工作首次发现，DREF是细胞先天免疫反应的一个组成部分，在病毒驱动的细胞重编程过程中，它通过E1A改变其SUMO化而被解除调节。我的实验室还表明，E1 A利用FUBP 1来抑制细胞应激反应途径，将FUBP 1锁定在与细胞应激调节因子p53的复合物中，阻止p53发挥其功能。这些研究只是触及了DREF和FUBP 1的途径和功能的表面，为进一步的研究铺平了道路。 对E1A结合蛋白的研究不仅告诉我们关于E1A的信息，还告诉我们与之结合的蛋白质的信息。重要的是，发现新的E1A结合蛋白可以确定关键的细胞枢纽，可以使用这种强大的病毒工具进行研究。我的研究项目主要集中在细胞中枢蛋白的识别和表征，以更好地了解它们在真核生物细胞过程中的作用。在短期内，对DREF和FUBP 1及其与E1A相关性的研究将阐明它们的细胞功能，并阐明它们被病毒靶向的原因。