Proteolytic Mechanisms Mediating Diverse Non-Apoptotic Caspase Functions

项目摘要 新的研究结果表明，在不同的动物门的半胱天冬酶的关键非凋亡功能。我 未发表的研究结果表明，半胱天冬酶在确保发育的多个方面发挥着重要作用。 包括细胞间通讯、细胞迁移、蛋白质稳态和调节蛋白质的翻译。 以组织特异性方式对基因子集进行修饰。此外，我的数据表明，在细胞中表达的半胱天冬酶靶点， 与半胱天冬酶同时作用的同一细胞可能不会受到半胱天冬酶的作用， 发育时间点提示额外的监管层。目前尚不清楚具体的非- 凋亡半胱天冬酶功能以这种动态方式介导。根据我最近的发现， 很可能半胱天冬酶需要其他组分，如E3连接酶，来执行非凋亡功能。我 因此，我假设半胱天冬酶与其他蛋白质复合起作用， 根据发育阶段、组织类型和环境状态的特异性。在未来五 多年来，我的实验室的关键目标是：1）确定半胱天冬酶介导的调节网络， 生命力，2）了解蛋白质-蛋白质相互作用如何影响不同的半胱天冬酶机制，以及3） 确定介导组织特异性翻译调节的caspase靶点。我发起了一项重要的 与我们在UT西南的生物物理学核心合作，大力开展结构-功能 半胱天冬酶与UBR型E3连接酶和其他组分的研究。我提议的跨学科研究 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保守的机制，指导非- 凋亡半胱天冬酶功能。

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 My unpublished findings indicate marked roles for caspases in ensuring multiple aspects of development including cell-cell communication, cell migration, protein homeostasis,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.