Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response
Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response
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DOI：
10.1152/ajpgi.2000.279.5.g961
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发表时间：
2000-11-01
影响因子：
4.5
通讯作者：
Perlmutter, DH
中科院分区：
文献类型：
--
作者：
Teckman, JH;Perlmutter, DH
尽管有证据表明，内质网（ER）中错误折叠蛋白的积累会导致特定的亚细胞形态变化，但尚不清楚这些形态变化是否是刻板的，或者它们是否取决于保留的特定错误折叠蛋白。这个问题对于突变分泌蛋白 α (1)-抗胰蛋白酶 (α (1)AT) Z 可能特别重要，因为这种突变蛋白保留在 ER 中会导致严重的靶器官损伤，即与 α (1)AT 缺乏相关的慢性肝炎/肝细胞癌。在这里，我们检查了为表达和保留突变型 α (1)ATZ 而设计的人类成纤维细胞以及来自三名 α (1)AT 缺陷患者的人类肝脏中发生的形态变化。除了内质网显着扩张之外，还存在强烈的自噬反应。通过免疫电子显微镜在自噬体中检测到突变的α(1)ATZ分子，并且自噬的化学抑制剂部分减少了α(1)ATZ的细胞内降解。与突变体CFTR Delta F508相反，突变体α(1)ATZ在异源细胞中的表达不会导致聚集体的形成。这些结果表明，突变型 α 1ATZ 的 ER 保留与显着的自噬反应相关，并提出自噬代表 α (1)AT 缺陷患者的肝脏试图保护自身免受损伤和癌变的一种机制的可能性。
Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), it is not clear whether these morphological changes are stereotypical or if they depend on the specific misfolded protein retained. This issue may be particularly important for mutant secretory protein alpha (1)-antitrypsin (alpha (1)AT) Z because retention of this mutant protein in the ER can cause severe target organ injury, the chronic hepatitis/hepatocellular carcinoma associated with alpha (1)AT deficiency. Here we examined the morphological changes that occur in human fibroblasts engineered for expression and ER retention of mutant alpha (1)ATZ and in human liver from three alpha (1)AT-deficient patients. In addition to marked expansion and dilatation of ER, there was an intense autophagic response. Mutant alpha (1)ATZ molecules were detected in autophagosomes by immune electron microscopy, and intracellular degradation of alpha (1)ATZ was partially reduced by chemical inhibitors of autophagy. In contrast to mutant CFTR Delta F508, expression of mutant alpha (1)ATZ in heterologous cells did not result in the formation of aggresomes. These results show that ER retention of mutant alpha 1ATZ is associated with a marked autophagic response and raise the possibility that autophagy represents a mechanism by which liver of alpha (1)AT-deficient patients attempts to protect itself from injury and carcinogenesis.