Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway
Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway
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肝囊肿素缺乏通过 mTOR 依赖性途径诱导自噬
DOI：
10.4161/auto.7.7.15822
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发表时间：
2011-07-01
期刊：
影响因子：
13.3
通讯作者：
Zhu, Wei-Guo
中科院分区：
文献类型：
--
作者：
Yang, Jing;Zhao, Ying;Zhu, Wei-Guo
编码肝囊蛋白/80K-H(PRKCSH)的基因突变可导致常染色体显性遗传性多囊肝病(ADPLD)。肝囊素作为葡萄糖苷酶II(Glu II)的非催化β亚基参与了新生糖蛋白的加工，并通过1，4，5-三磷酸肌醇受体(IP3R)调节内质网(ER)的钙释放。然而，关于细胞如何应对缺乏肝囊藻毒素的反应，人们知之甚少。在这项研究中，我们证明了敲除肝囊藻毒素诱导自噬，这是细胞内的主要降解途径，对细胞健康至关重要。异位表达野生型肝囊藻毒素，而不是致病突变体，挽救了siRNA诱导的效应。我们的数据表明，肝囊藻毒素缺乏诱导的自噬是通过哺乳动物的雷帕霉素靶标(MTOR)介导的。尽管导致Glu II活性的严重降低，但未折叠蛋白反应(UPR)途径并未受到干扰。此外，抑制IP3R介导的瞬时钙流动不是诱导自噬所必需的。这些结果为了解肝细胞素的功能和自噬的调节提供了新的见解。
Mutations in the gene encoding hepatocystin/80K-H (PRKCSH) cause autosomal-dominant polycystic liver disease (ADPLD). Hepatocystin functions in the processing of nascent glycoproteins as the noncatalytic beta subunit of glucosidase II (Glu II) and regulates calcium release from endoplasmic reticulum (ER) through the inositol 1,4,5-trisphosphate receptor (IP3R). Little is known, however, on how cells respond to a deficiency of hepatocystin. In this study, we demonstrate that knockdown of hepatocystin induces autophagy, the major intracellular degradation pathway essential for cellular health. Ectopic expression of wild-type hepatocystin, but not pathogenic mutants, rescues the siRNA-induced effect. Our data indicate that the induction of autophagy by hepatocystin deficiency is mediated through mammalian target of rapamycin (mTOR). Despite the resulting severe reduction in Glu II activity, the unfolded protein response (UPR) pathway is not disturbed. Furthermore, the inhibition of IP3R-mediated transient calcium flux is not required for the induction of autophagy. These results provide new insights into the function of hepatocysin and the regulation of autophagy.