Exploiting bacterial effector proteins to study human ubiquitin signaling

项目摘要 通过泛素化的翻译后信号传导对所有真核生物都是必不可少的， 过程可能导致严重的疾病。泛蛋白信号在许多领域的深远重要性 细胞过程源于其形成一组不同的聚合链的能力， 结果。泛素信号的复杂性大大超过了我们对其调控的理解， 细胞结果。虽然一些泛素链类型的信号作用是已知的（例如蛋白质降解 或细胞周期调控），许多所谓的“非典型”链的功能仍然是一个谜，尽管 几十年的研究。作为研究基础人类生物学的另一种方法，我们研究了 入侵病原菌和宿主泛素信号网络之间的相互作用。除了一 一系列其他泛素靶向活性，以支持感染细菌已经进化分泌效应蛋白 组装和去除宿主泛素信号，在某些情况下， 泛素链类型。我们认为，泛素靶向的细菌效应器代表了丰富的机会， 从“由外向内”的角度研究人类泛素信号传导。为了探索这个机会，我们 开发了一种多管齐下的方法，已经确定了新的泛素靶向活动， 细菌病原体使用结构和生物化学的方法，我们将解释的机制， 这些细菌酶的特异性，在这一点上，他们将被用作案例研究和工具，以扩大 我们的工作对破译的监管和信号的复杂性，人类遍在蛋白系统。我们 创新的方法来研究泛素生物学发挥了我们的优势，在其生化机制， 调控，并利用强大的进化压力放在细菌篡夺特定方面的主机 泛素信号在接下来的五年里，我们将展示细菌泛素靶向的广泛性。 活动和他们的实用性，解剖错综复杂的泛素信号，这有助于我们更大的视野， 了解细菌干扰宿主信号传导过程的动机和后果。

Project Summary Post-translational signaling through ubiquitination is essential to all eukaryotic life, and dysregulation of this process can lead to severe forms of disease. The far-reaching importance of ubiquitin signaling across many cellular processes stems from its ability to form a diverse set of polymeric chains that signal for distinct outcomes. The complexity of ubiquitin signaling vastly outweighs our understanding of its regulation and cellular outcomes. While the signaling roles for some ubiquitin chain types are known (e.g. protein degradation or cell cycle regulation), the functions of many so-called `atypical' chains have remained a mystery despite decades of research. As an alternative approach to studying fundamental human biology, we study the interactions between invading pathogenic bacteria and the host ubiquitin signaling network. In addition to a range of other ubiquitin-targeted activities, to support infection bacteria have evolved secreted effector proteins to assemble and remove host ubiquitin signals, in some cases with exquisite specificity toward discrete ubiquitin chain types. We propose that ubiquitin-targeted bacterial effectors represent a rich opportunity to study human ubiquitin signaling from an `outside-in' perspective. To explore this opportunity, we have developed a multipronged approach that has identified novel ubiquitin-targeted activities among important bacterial pathogens. Using structural and biochemical approaches we will explain the mechanisms and specificities of these bacterial enzymes, at which point they will be used as case studies and tools to extend our work toward deciphering the regulatory and signaling complexities of the human ubiquitin system. Our innovative approach to studying ubiquitin biology plays to our strengths in the biochemical mechanisms of its regulation, and leverages the strong evolutionary pressure placed on bacteria to usurp specific aspects of host ubiquitin signaling. Over the next five years we will demonstrate the breadth of bacterial ubiquitin-targeted activities and their utility for dissecting the intricacies of ubiquitin signaling, which feeds into our larger vision of understanding the motivations and ramifications of bacterial interference in host signaling processes.