Regulation of ER-nuclear communication by CREB3 transmembrane transcription factors

我们的细胞执行广泛的功能，其中一些是共同的，一些是每种细胞类型的不同功能。例如，我们胰腺中的某些细胞感知代谢信号并调节胰岛素的分泌，以控制血糖的变化。胰腺中的不同细胞在酶的分泌中发挥作用，这些酶有助于分解摄入的食物。发育中的骨骼细胞分泌组成骨基质的成分，而我们血液系统的细胞则产生和分泌抗体来对抗感染。这些特定的例子反映了本应用所涉及的一个共同的关键功能，即适当地控制分泌和分泌功能。分泌途径由一个特殊的器官控制，称为内质网(ER)。这种膜结合细胞器的协调网络最终负责所有蛋白质和其他成分的一般性和细胞型特异性分泌，这些蛋白质和其他成分执行上述例子中的不同功能。因此，内质网通路功能障碍与多种重要的人类疾病有关。例如糖尿病和血脂紊乱，与骨形成缺陷相关的疾病，以及与分泌物功能障碍和肠道炎症相关的疾病，如溃疡性柯里炎。尽管与人类疾病的联系已经确立，但调控ER功能及其在正常过程和疾病进展中的作用的详细机制的许多方面仍然知之甚少。细胞功能的一般特征是动态平衡的过程，即通过反馈控制系统调节内部条件，以稳定细胞的健康和正常功能，以响应不断变化的条件。这一过程经常涉及到基因表达的控制。内质网中有一条特殊的动态平衡途径，用于控制我们体内的胆固醇水平。在这一途径中，转录因子在物理上与内质网相关，在内质网中，它感知胆固醇的变化，结果被加工并运输到细胞核，以刺激胆固醇的产生。对这一途径的了解对了解健康和疾病中的胆固醇平衡和失衡有很大帮助。通过我们的工作，我们现在知道还有其他因子，称为CREB3蛋白，也物理上锚定在内质网中，通过将信息传递回细胞核来控制适应性反应。最近的研究表明，它们在内质网发挥着重要功能，例如，在发育骨细胞、正常软骨形成以及在肝脏中控制分泌的脂肪酸和甘油三酯水平方面都是必需的。然而，我们对它们是如何发挥作用的机械性理解很少。这项建议的主要目的是了解控制CREB3活性的详细机制，以及它们如何调节这些不同的下游途径。我们将解决两个主要目标；首先，了解控制这些因子如何保留在内质网中的信号通路，以及它们如何被释放和运输到细胞核；其次，它们与什么蛋白质相互作用来决定细胞的整体定位，阐明控制CREB3蛋白的机制及其对适应性反应的转录调控，将有助于我们理解ER生物学和重要的生理途径，并可能对人口中重大负担的疾病过程有新的见解。了解它们的作用和功能也可能有应用，例如在操纵分泌途径以增加所需产品的产量方面。

Our cells carry out a broad range of functions, some of which are common and some distinct for each cell type. As examples, certain cells in our pancreas sense metabolic signals and regulate secretion of insulin to control variations in blood glucose. Different cells in the pancreas play a role in the secretion of enzymes that help breakdown ingested foodstuffs. Cells within developing bone secrete components that build bone matrix, while cells of our blood system produce and secrete antibodies to combat infection. These particular examples reflect a common critical function with which this application is concerned, namely the proper control of secretion and secretory function. The secretory pathway is controlled by a specialized apparatus, termed the endoplasmic reticulum (ER). This coordinated network of membrane-bound organelles is ultimately responsible for the general and cell-type specific secretion of all the proteins and other components that carry out the diverse functions in the examples above. Therefore, malfunction of ER pathways is associated with a wide range of important human diseases. Examples include diabetes and lipid disorders, conditions associated with defective bone formation, and diseases associated with malfunction in secretion and inflammation in the intestine such as ulcerative coilitis. Although the links with human disease are well established, many aspects of the detailed mechanisms regulating ER functions and their role in normal processes and disease progression remain poorly understood. A general feature of cellular function is the process of homeostasis, i.e. the regulation of internal conditions by a system of feedback controls to stabilize the health and proper functioning of the cell in response to changing conditions. This process frequently involves the control of gene expression. A specialized homeostatic pathway occurs in the ER for the control of cholesterol levels in our bodies. In this pathway a transcription factor is physically associated with the ER, where it senses alterations in cholesterol, and as a result is processed and transported to the nucleus to stimulate cholesterol production. Knowledge of this pathway has contributed significantly to understanding cholesterol balance and imbalance in health and disease.Through our work, we now know there are additional factors, called CREB3 proteins, that are also physically anchored in the ER and control adaptive responses by relaying information back to the nucleus. Recent work has demonstrated that they play vital functions at the ER and are required, for example, in developing bone cells, for normal cartilage formation, and in liver for the control of secreted fatty acid and triglyceride levels. However we have very little mechanistic understanding of how they function. The principle aims of this proposal are to understand the detailed mechanisms controlling CREB3 activity and how they regulate these distinct downstream pathways. We will address two main objectives; firstly understanding the signalling pathways that control how these factors are retained in the ER and how they are released and transported to the nucleus; secondly, what proteins they interact with to dictate cellular localisation Overall, elucidation of the mechanisms controlling CREB3 proteins and their transcriptional regulation of adaptive responses will contribute significantly to our understanding of ER biology and important physiological pathways and potentially yield new insight into disease processes of significant burden in the population. Understanding their role and function may also have application e.g., in manipulating the secretory pathway to increase production of desired products.