Regulation of intracellular HTRA1 protease

HtrA家族代表了一类独特的寡聚丝氨酸蛋白酶。它们的特征是催化结构域与C-末端PDZ结构域的结合，以及非活性构象和活性构象之间的转换是可逆的。尽管人类HTRA1与几种严重的病理疾病有关，如癌症、老年性黄斑变性、阿尔茨海默病、关节炎和家族性缺血性脑小血管疾病，但对于这种蛋白水解酶在细胞中是如何调节的几乎一无所知。因此，这项建议的主要目标是确定和分析参与调节细胞质HTRA1活性的细胞因素，并描述相应的生理后果。为了确定潜在的分子机制，我们将研究HTRA1与其调节配体之间的蛋白质复合体以及翻译后修饰。这些数据将使我们能够解决重要的问题，在细胞过程中，HTRA1的调节特别重要。相应地，这些研究有望揭示这种广泛保守的蛋白水解酶在人类细胞蛋白质动态平衡中的作用。

The HtrA family represents a unique class of oligomeric serine proteases. Their defining features are the combination of a catalytic domain with C-terminal PDZ domains and that the switch between the inactive and active conformations is reversible. Even though human HTRA1 is implicated in several severe pathologies such as cancer, age-related macular degeneration, Alzheimer's disease, arthritis and familial ischemic cerebral small-vessel disease, close to nothing is known about how this protease is regulated in the cell. The main objective of this proposal is therefore to identify and analyse cellular factors involved in regulating the activity of cytoplasmic HTRA1 and to characterise the corresponding physiologic consequences. To identify the underlying molecular mechanisms, protein complexes between HTRA1 and its regulatory ligands as well as posttranslational modifications will be studied. These data will allow us to address the important question in which cellular processes the regulation of HTRA1 is of particular importance. Correspondingly, these studies are expected to reveal deeper insights into the roles of this widely conserved protease in protein homeostasis of human cells.