Linking alpha1-antitrypsin phase transition with cellular health

α - 1抗胰蛋白酶是一种在肝脏中产生的蛋白质，它在血液中循环，以控制肺部的炎症。一些患有α - 1抗胰蛋白酶缺乏症的人患肝脏和肺部疾病的风险更高，因为他们遗传了α - 1抗胰蛋白酶的一种突变形式，这种突变形式在肝细胞中积累，无法进入血液。这种不正常的抗胰蛋白酶在细胞的内质网（简称ER）内积聚。这种积累会增加肝硬化（疤痕）和肝癌的风险。目前除了肝移植，没有其他治疗方法可以帮助治疗这种形式的肝病。我们研究α - 1抗胰蛋白酶在内质网内的积累，以便我们开发新的肝保护治疗方法。当内质网出现故障时，许多人类疾病都可能出现，即所谓的内质网应激。内质网的作用是制造分泌的蛋白质，比如抗胰蛋白酶，使新合成的蛋白质“折叠”成它们独特的形状，从而使它们在体内发挥特定的作用。内质网应激发生在内质网蛋白不能正确折叠时，这可能发生在一些突变蛋白上。这会导致内质网蛋白随机地粘在一起，破坏细胞。相比之下，最常见的α - 1抗胰蛋白酶突变形式形成有序的聚合物链，似乎不会直接引起内质网应激。相反，它们使细胞对其他压力更敏感，比如饱和脂肪或酒精，它们更容易引发内质网压力。抗胰蛋白酶聚合物导致这种敏感性增加的原因尚不清楚，但我们最近发现，抗胰蛋白酶聚合物可以在内质网内部固化，形成一种多孔材料，可以捕获较大的内质网蛋白，同时允许较小的内质网蛋白通过。这种“分子过滤”可能会阻止大的内质网蛋白移动到需要它们的地方，这可能是内质网应激敏感性增加的原因。重要的是，我们发现内质网中的一些蛋白质驱动抗胰蛋白酶的凝固，并且可以通过阻断细胞内的某些信号通路来阻止这种凝固。在目前的项目中，我们的目标是确定哪些细胞蛋白负责抗胰蛋白酶的凝固。我们还将确定抗胰蛋白酶的凝固如何影响细胞的健康。最后，我们将利用这些知识来开发治疗方法，以保护肝细胞免受α - 1抗胰蛋白酶突变的毒性作用。

Alpha1-antitrypsin is a protein made in the liver that circulates in the blood to control inflammation in the lungs. Some people with a condition call alpha1-antitrypsin deficiency are at increased risk of liver and lung disease because they have inherited a mutated form of alpha1-antitrypsin that accumulates in liver cells and fails to reach the blood. This abnormal antitrypsin, builds up inside a part of the cell called the endoplasmic reticulum (or ER for short). This build-up then increases the risk of liver cirrhosis (scarring) and liver cancer. No current treatments apart from liver transplantation can help in this form of liver disease. We study the accumulation of alpha1-antitrypsin inside the ER so that we can develop new liver-protective treatments.Many human diseases can arise when the ER malfunctions: so-called ER stress. The job of the ER is to make secreted proteins, like antitrypsin, allowing newly made proteins to "fold" into their unique shape that allows them to perform their specific roles in the body. ER stress happens when ER proteins fail to fold correctly, which can happen with some mutated proteins. This causes ER proteins to stick together randomly, damaging the cell. By contrast, the most common mutated form of alpha1-antitrypsin forms ordered chains of polymers that do not appear to cause ER stress directly. Instead, they make the cell more sensitive to other stresses, such as saturated fats or alcohol, which can trigger ER stress more easily. The reason why polymers of antitrypsin cause this increased sensitivity is unknown, but we recently discovered that antitrypsin polymers can solidify inside the ER to forming a porous material that traps large ER proteins while allowing smaller ones to pass through. This "molecular filtration" may prevent large ER proteins moving to where they are required and this may account for the increased sensitivity to ER stress. Importantly, we discovered that some proteins in the ER drive this solidification of antitrypsin and can be prevented from doing so by blocking certain signalling pathways inside the cell.In the current project, we aim to identify which cellular proteins are responsible for the solidification of antitrypsin. We will also determine how the solidification of antitrypsin affects the health of cells. Finally, we will use this knowledge to develop therapies to protect liver cells from the toxic effects of alpha1-antitrypsin mutations.