Characterization of a novel stress-regulated anti-apoptotic ubiquitin ligase

描述（由申请人提供）：尽管细胞对遗传毒性（DNA损伤）或ER应激的反应是复杂的，但它们对细胞稳态至关重要。细胞对这些压力的反应异常可能产生深远的影响，导致重大异常，包括癌症、心血管异常、糖尿病和神经退行性疾病。本申请是为了表征我们命名为BBEL 1（Bax和巴克相互作用E3连接酶1）的新基因。BBEL1编码一种新的应激调节E3泛素连接酶，定位于线粒体。BBEL 1抑制DNA损伤诱导的细胞凋亡，并与促凋亡的Bax和巴克相互作用。我们假设BBEL 1是一种新型的线粒体抗凋亡E3泛素连接酶，通过抑制Bax和巴克介导其抗凋亡作用，因此是细胞应激反应途径中的关键组分。我们提出了三个具体目标，以进一步表征BBEL 1。具体目标1是确定BBEL 1的拓扑结构和定位。具体目标2是研究Bax和巴克与BBEL 1相互作用的分子基础。具体目标3是进行BBEL 1的结构功能表征。拟议的研究是表征BBEL 1的关键初始步骤，并为进一步深入研究奠定基础，旨在确定这种新型泛素连接酶的确切功能，特别是在人类疾病的毒理学和病理学方面。细胞对DNA损伤和其他类型压力的反应是复杂的，但对细胞健康非常重要。细胞对这些压力的反应缺陷可能产生深远的影响，导致重大异常，包括癌症、心血管异常、糖尿病和神经退行性疾病。在这里，我们提出了一个新的基因BBEL1的特点，编码一种新的应力调节E3泛素连接酶。BBEL 1似乎是细胞应激反应途径的关键组分，因为它抑制DNA损伤诱导的凋亡并与促凋亡蛋白相互作用。拟议的研究是表征BBEL 1的关键初始步骤，并为进一步深入研究奠定基础，旨在确定这种新型泛素连接酶的确切功能，特别是在人类疾病的毒理学和病理学方面。

DESCRIPTION (provided by applicant): Although cellular responses to genotoxic (DNA damage) or ER stress are complex, they are vital for cellular homeostasis. Aberrations in cellular responses to these stresses can have profound effects giving rise to major abnormalities including cancer, cardiovascular anomalies, diabetes and neurodegenerative disorders. This application is to characterize a novel gene that we have named BBEL1 (Bax and Bak interacting E3 Ligase 1). BBEL1 encodes a novel stress-regulated E3 ubiquitin ligase that localizes to mitochondria. BBEL1 inhibits DNA damage-induced apoptosis and interacts with the pro-apoptotic Bax and Bak. We hypothesize that BBEL1 is a novel mitochondrial anti-apoptotic E3 ubiquitin ligase that mediates its anti-apoptotic effects by inhibiting Bax and Bak and thus, a key component in the cellular stress response pathways. We are proposing three specific aims to further characterize BBEL1. Specific Aim 1 is to determine the topology and localization of BBEL1. Specific Aim 2 is to investigate the molecular basis for Bax and Bak interactions with BBEL1. Specific Aim 3 is to perform structural functional characterization of BBEL1. Proposed studies are critical initial steps to characterize BBEL1 and to lay the groundwork for further in-depth studies aiming to determine the exact function of this novel ubiquitin ligase particularly in context to toxicology and pathobiology of human diseases. PUBLIC HEALTH RELEVANCE: Cellular responses to DNA damage and other types of stresses are complex yet very vital for cellular wellbeing. Defects in cellular responses to these stresses can have profound effects giving rise to major abnormalities including cancer, cardiovascular anomalies, diabetes and neurodegenerative disorders. Here we propose to characterize a novel gene BBEL1 that encodes a novel stress-regulated E3 ubiquitin ligase. BBEL1 appears to be a key component of cellular stress response pathways as it inhibits DNA damage-induced apoptosis and interacts with pro-apoptotic proteins. Proposed studies are critical initial steps to characterize BBEL1 and to lay the groundwork for further in-depth studies aiming to determine the exact function of this novel ubiquitin ligase particularly in context to toxicology and pathobiology of human diseases.