α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.

中文翻译：

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钙网蛋白增强错误折叠的 α-1-抗胰蛋白酶的分泌运输

α1-抗胰蛋白酶 (AAT) 调节肺和肝脏中多种蛋白酶的活性。AAT (E342K) 的突变体 ATZ 会形成聚合物，该聚合物在血清中的含量很低，并会诱导细胞内蛋白质内含物，导致肺气肿和肝硬化。了解可以减少 ATZ 细胞内积累的因素非常有意义。我们现在表明，钙网蛋白 (CRT) 是一种内质网 (ER) 糖蛋白伴侣，可促进 ATZ 的分泌运输，从而提高介质与细胞的比例。ATZ 的这种效应比 AAT 更明显，并且仅部分依赖于 CRT 的聚糖结合位点，这通常与 CRT 的底物募集和折叠相关。CRT 相关的伴侣钙连接蛋白不会增强 ATZ 的分泌运输，尽管钙联蛋白-ATZ复合物的细胞丰度较高。CRT 缺陷改变了 ATZ-ER 伴侣复合物的分布，增加了 ATZ-BiP 结合和包涵体形成，并减少了 ATZ 与 ER-高尔基体运输所需成分的相互作用，这与 CRT 缺陷细胞中蛋白质转运蛋白 Sec31A 水平的降低相一致。这些发现表明 CRT 在促进形成聚合物和大细胞内包涵体的蛋白质的分泌运输方面具有新作用。在缺乏 CRT 的情况下 ATZ 的低效分泌运输与 ER 衍生的 ATZ 包涵体的积累增加同时发生。进一步了解控制 ATZ 分泌运输的因素及其通过 CRT 的调节可能会导致与 AAT 缺乏相关的肺和肝疾病的新疗法。