Exploiting bacterial effector proteins to study human ubiquitin signaling

项目摘要 翻译后信号通过泛素化对所有真核生物都是必不可少的，而这一过程的失调 这一过程可能会导致严重的疾病形式。泛素信号在许多领域的深远重要性 细胞过程源于它能够形成一组不同的聚合链，这些聚合链发出不同的信号 结果。泛素信号的复杂性远远超过了我们对其调控和 细胞结果。虽然某些泛素链类型的信号作用是已知的(例如，蛋白质降解 或细胞周期调节)，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 入侵病原菌与寄主泛素信号网络之间的相互作用。除了 其他一系列泛素靶向活性，支持感染细菌进化出分泌型效应蛋白 组装和移除宿主泛素信号，在某些情况下具有对离散的精致特异性 泛素链类型。我们认为，泛素靶向的细菌效应器代表着一个丰富的机会 从“由外而内”的角度研究人类泛素信号。为了探索这个机会，我们有 开发了一种多管齐下的方法，确定了新的泛素靶向活动，包括 细菌病原体。使用结构和生化方法，我们将解释机制和 这些细菌酶的特殊性，在这一点上，它们将被用作案例研究和工具，以扩展 我们为破译人类泛素系统的调控和信号复杂性所做的工作。我们的 研究泛素生物学的创新方法在其生化机制上发挥了我们的优势 调节，并利用施加在细菌身上的强大进化压力来篡夺宿主的特定方面 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度 活动及其对解剖复杂的泛素信号的效用，这将为我们更大的愿景提供支持 了解细菌干扰宿主信号过程的动机和后果。

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.