Perlmutter David H
Department of Pediatrics and Cell Biology, University of Pittsburgh School of Medicine, Childrens Hospital of Pittsburgh, Pynnsylvania 15213, USA.
Autophagy. 2006 Oct-Dec;2(4):258-63. doi: 10.4161/auto.2882. Epub 2006 Oct 5.
In the classical form of alpha-1-antitrypsin (AT) deficiency a point mutation renders aggregation-prone properties on a hepatic secretory protein. The mutant ATZ protein in retained in the endoplasmic reticulum (ER) of liver cells rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows the neutrophil proteases to slowly destroy the connective tissue matrix of the lung, resulting in premature development of pulmonary emphysema as early as the third decade of life. A gain-of-toxic function mechanism is responsible for liver inflammation and carcinogenesis. Indeed this deficiency is the most common genetic cause of liver disease in children in the US. It also causes chronic liver inflammation and carcinoma that manifests itself later in life. However, the majority of affected homozygotes apparently escape liver disease. This last observation has led to the concept that genetic and/or environmental modifiers affect the disposal of mutant ATZ within the ER or affect the protective cellular responses activated by accumulation of ATZ in the ER and, in turn, these modifiers determine which homozygotes develop liver inflammation and carcinoma. In this article I review a series of studies published over the last six years showing that autophagy is specifically activated by ER accumulation of ATZ and that it plays a critical role in the disposal of this mutant protein. Indeed, the most recent studies suggest that there is specialization of the autophagic pathway in that it is specifically activated by, and designed for disposal of, the aggregated forms of ATZ while the proteasome is specialized for disposal of soluble forms of ATZ. Together, these studies provide further evidence for the importance of autophagy in the cellular adaptive response to aggregated proteins in general.
在α-1抗胰蛋白酶（AT）缺乏的经典形式中，一个点突变赋予了一种肝脏分泌蛋白易于聚集的特性。突变的ATZ蛋白保留在肝细胞的内质网（ER）中，而不是分泌到血液和体液中，它通常在血液和体液中作为中性粒细胞蛋白酶的抑制剂发挥作用。功能丧失机制使中性粒细胞蛋白酶能够缓慢破坏肺的结缔组织基质，导致早在生命的第三个十年就过早出现肺气肿。功能获得性毒性机制则导致肝脏炎症和致癌作用。事实上，这种缺乏症是美国儿童肝病最常见的遗传原因。它还会导致慢性肝脏炎症和癌症，这些疾病在生命后期表现出来。然而，大多数受影响的纯合子显然没有患肝病。最后这一观察结果引出了这样一个概念，即遗传和/或环境修饰因子会影响内质网中突变ATZ的处理，或者影响由内质网中ATZ积累激活的细胞保护反应，反过来，这些修饰因子决定哪些纯合子会发展为肝脏炎症和癌症。在本文中，我回顾了过去六年发表的一系列研究，这些研究表明自噬是由内质网中ATZ的积累特异性激活的，并且它在处理这种突变蛋白中起关键作用。事实上，最近的研究表明自噬途径存在特异性，即它是由聚集形式的ATZ特异性激活并专门用于处理聚集形式的ATZ，而蛋白酶体则专门用于处理可溶性形式的ATZ。总之，这些研究进一步证明了自噬在细胞对聚集蛋白的适应性反应中的重要性。
