Cellular functions of hub proteins and their deregulation by adenovirus

蜂窝监管网络本质上是冗余的，代表着一个抵抗中断的多节点无标度网络。这种类型的组织是必要的，以避免在单个节点中断时出现严重的网络故障。细胞调节网络的内在弱点在于网络功能的关键调节因子，即所谓的“中枢蛋白”。病毒已经进化出以这些集线器为目标的巧妙方法，以重塑网络并实现病毒传播和主机逃避。因此，利用病毒蛋白来重塑细胞提供了一种有用的手段来识别重要过程的关键细胞调节因子。我已经通过与腺病毒即刻早期基因产物E1a结合而鉴定出两种新的细胞调节因子：DREF和FUBP1。这两种蛋白质都鲜为人知，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。FUBP1是一种蛋白质，通过与基因调控区内的增强子结合并调节蛋白质翻译，似乎在转录调控中发挥作用。腺病毒的E1a蛋白是一种由289个氨基酸组成的小蛋白，其最大的异构体。E1a可以被认为是一个“中枢探测器”，因为它有能力瞄准关键的细胞调节因子。E1a在研究和理解各种各样的细胞过程中一直是一个宝贵的工具。最近由NSERC资助的我的实验室的研究已经开始揭开细胞中心蛋白的神秘面纱。我们已经发现了DREF和FUBP1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。我在实验室的工作首次证实，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新编程过程中，它通过改变其SUMO化而被解除调控。我的实验室还表明，E1a通过将FUBP1与细胞应激调节因子P53结合起来，将FUBP1锁定在一个复合体中，从而阻止P53发挥其功能，从而抑制了细胞应激反应途径。这些研究只是触及了DREF和FUBP1的通路和功能的表面，为进一步的研究铺平了道路。对E1a结合蛋白的研究不仅让我们了解了E1a，还让我们了解了与E1a结合的蛋白质。重要的是，新的E1a结合蛋白的发现确定了关键的细胞中心，可以使用这种强大的病毒工具进行研究。我的研究项目集中在细胞中心蛋白的鉴定和特性上，以更好地了解它们在控制真核生物生命的细胞过程中的作用。短期内，对DREF和FUBP1及其与E1a的关联的研究将澄清它们的细胞功能，并阐明它们被病毒靶向的原因。

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.