title: Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway.
abstract: 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.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Fen-Jun
authors.initials: FJ
authors.lastname: Jiang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liao
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Tu
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xie
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D020134:Catalytic Domain; D055785:Gene Knockdown Techniques; D005959:Glucosidases / Q000172:deficiency* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056811:Unfolded Protein Response; D000520:alpha-Glucosidases / Q000172:deficiency / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047908:Intracellular Signaling Peptides and Proteins; D058570:TOR Serine-Threonine Kinases; C034251:4-nitrophenyl-alpha-glucosidase; D005959:Glucosidases; C070368:PRKCSH protein, human; D000520:alpha-Glucosidases; D002118:Calcium