Proteolytic Mechanisms Mediating Diverse Non-Apoptotic Caspase Functions

项目摘要 新的发现表明，caspase在不同的动物门中具有关键的非凋亡功能。我的 未发表的研究结果表明，caspase在确保发育的多个方面发挥了显著作用。 包括细胞间的通讯、细胞迁移、蛋白质的动态平衡和调节蛋白的翻译。 以特定于组织的方式表达基因的子集。此外，我的数据显示，一个caspase靶标在 与caspase同时作用的同一细胞可能不会被caspase作用，直到特定的 发育时间点暗示了额外的监管层面。目前尚不清楚具体的非 凋亡的caspase功能是以这样一种动态的方式介导的。根据我最近的发现，这是 很可能caspase需要其他成分，如E3连接酶，才能执行非凋亡功能。我 因此假设半胱氨酸天冬氨酸氨基转移酶在与其他蛋白质的复合体中发挥作用，从而赋予非凋亡性 根据发育阶段、组织类型和环境状况的特异性。在接下来的五年里 几年来，我的实验室的关键目标是：1)确定caspase介导的调控网络支持 活力，2)了解蛋白质-蛋白质相互作用如何影响不同的caspase机制，以及3) 确定介导组织特异性翻译调控的caspase靶点。我发起了一项重要的 与德克萨斯大学西南分校的生物物理学核心合作，大力承担结构功能 含UBr型E3连接酶及其他组分的半胱氨酸酶的研究。我建议的跨学科研究 包括遗传筛选、生化分析、翻译组学、蛋白质组学和结构-功能研究。 拟议研究的目的是了解引导非人类进化的保守机制 凋亡的caspase功能。

Project Summary Emerging findings show critical non-apoptotic functions of caspases across diverse animal phyla. My unpublished findings indicate marked roles for caspases in ensuring multiple aspects of development including cell-cell communication, cell migration, protein homeostasis, and regulating the translation of a subset of genes in a tissue-specific manner. Moreover, my data indicate that a caspase target expressed in the same cell at the same time as the caspase may not be acted upon by the caspase until a specific developmental time point suggesting additional layers of regulation. It is not known how specific non- apoptotic caspase functions are mediated in such a dynamic manner. Based on my recent findings, it is likely that caspases require other components, such as E3 ligases, to execute the non-apoptotic functions. I therefore hypothesize that caspases function in complexes with other proteins that confer non-apoptotic specificity according to developmental stage, tissue type, and environmental status. Over the next five years, the critical goals for my lab are to: 1) identify the caspase-mediated regulatory network supporting vitality, 2) understand how protein-protein interactions influence distinct caspase mechanisms, and 3) identify the caspase targets mediating tissue-specific translational regulation. I have initiated an important collaboration with our biophysics core at UT Southwestern to vigorously undertake structure-function studies of caspases with UBR-type E3 ligases and other components. My proposed interdisciplinary studies include genetic screens, biochemical analyses, translatomics, proteomics, and structure-function studies. The objective of the proposed studies is to understand the conserved mechanisms directing the non- apoptotic caspase functions.