Sequestration of mutated α1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function
Sequestration of mutated α1-antitrypsin into inclusion bodies is a cell-protective mechanism to maintain endoplasmic reticulum function
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DOI：
10.1091/mbc.e07-06-0587
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发表时间：
2008-02-01
影响因子：
3.3
通讯作者：
Baldini, Giulia
中科院分区：
文献类型：
--
作者：
Granell, Susana;Baldini, Giovanna;Baldini, Giulia
E342K突变的变异型α1-抗胰蛋白酶有很高的细胞内聚合物形成倾向，与肝脏疾病有关。在携带突变的个体的肝细胞中，α1-抗胰蛋白酶定位于内质网(ER)和膜包裹的包涵体(IBS)。目前还不清楚IBS是否会造成细胞毒性，或者它们是否对细胞具有保护作用。我们发现，在肝癌细胞中，突变的α1-抗胰蛋白酶离开内质网，积聚在自噬和溶酶体标记阴性的IBS中，并含有几种内质网成分，但不含钙粘连蛋白。突变的α1-抗胰蛋白酶也可在神经内分泌细胞中诱导IBS，表明这些细胞器的形成不是细胞类型特有的。在IBS存在的情况下，ER功能基本维持。钙粘蛋白水平的增加，而不是蛋白质二硫键异构酶的水平，抑制了IBS的形成，并导致突变的α1-抗胰蛋白酶保留在内质网中。在肝癌细胞中，Calnexin过表达导致突变的α1-抗胰蛋白酶定位向内质网转移，导致细胞萎缩、内质网应激和内质网水平的分泌途径受损。我们的结论是，突变的α1-抗胰蛋白酶从内质网分离到IBS是一种保护性细胞反应，以维持功能分泌途径。
A variant alpha 1-antitrypsin with E342K mutation has a high tendency to form intracellular polymers, and it is associated with liver disease. In the hepatocytes of individuals carrying the mutation, alpha 1-antitrypsin localizes both to the endoplasmic reticulum (ER) and to membrane-surrounded inclusion bodies (IBs). It is unclear whether the IBs contribute to cell toxicity or whether they are protective to the cell. We found that in hepatoma cells, mutated alpha 1-antitrypsin exited the ER and accumulated in IBs that were negative for autophagosomal and lysosomal markers, and contained several ER components, but not calnexin. Mutated alpha 1-antitrypsin induced IBs also in neuroendocrine cells, showing that formation of these organelles is not cell type specific. In the presence of IBs, ER function was largely maintained. Increased levels of calnexin, but not of protein disulfide isomerase, inhibited formation of IBs and lead to retention of mutated alpha 1-antitrypsin in the ER. In hepatoma cells, shift of mutated alpha 1-antitrypsin localization to the ER by calnexin overexpression lead to cell shrinkage, ER stress, and impairment of the secretory pathway at the ER level. We conclude that segregation of mutated alpha 1-antitrypsin from the ER to the IBs is a protective cell response to maintain a functional secretory pathway.