Regulation of synthesis, dimerisation and secretion of the amyloidogenic protease inhibitor cystatin C

组成我们组织的细胞嵌入在细胞外蛋白质（例如胶原蛋白）的复杂网格中，为组织提供支持，强度和弹性。这种细胞外基质不是静态的;当免疫系统的细胞通过间隙空间移动以监测组织的健康时，它会不断重塑。当发生感染或损伤时，发生的炎症反应以及组织修复过程也涉及细胞外基质组成的深刻变化。这些过程对肿瘤生长也很重要;癌细胞需要通过间隙空间清除它们的方式以逃逸到循环和转移。在所有这些过程中，细胞向细胞外间隙释放降解胶原蛋白和细胞外基质的其他组分的蛋白酶。显然，这些蛋白酶必须受到严格的调控，以防止它们失控，因此细胞也会产生蛋白酶的抑制剂。细胞外空间中所含的蛋白酶和抑制剂的量必须适当维持。如果这种平衡被破坏，这可能导致病理学。例如，动脉粥样硬化部分是由血管壁的过度蛋白水解引起的。在这个项目中，我们想要研究细胞外蛋白水解最丰富和最重要的抑制剂之一：半胱氨酸蛋白酶抑制剂C的机制。我们已经发现，免疫系统中的某些细胞称为树突状细胞，它们具有有趣的机制来调节它们分泌的胱抑素C的量。此外，这种机制之一，它包括配对的蛋白质，以产生无活性的二聚体，可能是一些疾病的原因，其特征是在细胞外空间的胱抑素C的积累。我们的研究可能使我们能够设计治疗与半胱氨酸蛋白酶抑制剂C的缺陷或过量产生相关的病理学的疗法。

The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also involve profound changes in the composition of the extracellular matrix. Such processes are also important for tumour growth; the cancer cells need to clear their way through interstitial space to escape to circulation and metastasize. During all these processes, the cells release to the extracellular space proteases that degrade collagen and the other components of the extracellular matrix. Obviously, these proteases must be tightly regulated to prevent them running out of control, so the cells also produce inhibitors of the proteases. The amount of proteases and inhibitors contained in the extracellular space must be maintained properly. If this equilibrium is disrupted, this can lead to pathology For instance, atherosclerosis is caused in part by excessive proteolysis of the blood vessel wall. In this project we want to study the mechanisms of one of the most abundant and important inhibitors of extracellular proteolysis: Cystatin C. We have discovered that certain cells of the immune system called dendritic cells posses interesting mechanisms to regulate how much Cystatin C they secrete. Furthermore, one of this mechanisms, which consists of pairing the protein to produce inactive dimers, may be the cause of some diseases characterised by accumulation of Cystatin C in the extracellular space. Our study may allow us to design therapies for the treatment of pathologies associated with defective or excessive production of Cystatin C.