Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
Autophagy (Impact Factor: 11.75). 07/2011; 7(7):748-59. DOI: 10.4161/auto.7.7.15822
Source: PubMed


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.

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Available from: Wei-Guo Zhu,
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    • "What kind of role autophagy is playing in these diverse liver pathologies is still largely unknown. Recently, we revealed that in polycystic liver disease (PCLD), autophagy is activated by the deficiency of hepatocystin, of which mutants have been shown to cause PCLD 141. Therefore, in PCLD, autophagy inhibition might be a strategy to delay pathogenesis. "
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