title: Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation.
abstract: Deficiency in autophagy, a lysosome-dependent cell degradation pathway, has been associated with a variety of diseases especially cancer. Recently, the activation of autophagy by hepatitis B virus X (HBx) protein, which is implicated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), has been identified in hepatic cells. However, the underlying mechanism and the relevance of HBx-activated autophagy to the carcinogenesis caused by HBV remain elusive. Here, by transfection of HBV genomic DNA and HBx in hepatic and hepatoma cells, we showed that HBV- or HBx-induced autophagosome formation was accompanied by unchanged MTOR (mechanistic target of rapamycin) activity and decreased degradation of LC3 and SQSTM1/p62, the typical autophagic cargo proteins. Further functional and morphological analysis indicated that HBx dramatically impaired lysosomal acidification leading to a drop in lysosomal degradative capacity and the accumulation of immature lysosomes possibly through interaction with V-ATPase affecting its lysosome targeting. Moreover, clinical specimen test showed increased SQSTM1 and immature lysosomal hydrolase CTSD (cathepsin D) in human liver tissues with chronic HBV infection and HBV-associated liver cancer. These data suggest that a repressive effect of HBx on lysosomal function is responsible for the inhibition of autophagic degradation, and this may be critical to the development of HBV-associated HCC.
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Mengdie
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Surgery; First Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, Zhejiang China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; First Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, Zhejiang China.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; First Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, Zhejiang China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology; Program in Molecular Cell Biology; Zhejiang University School of Medicine; Hangzhou, Zhejiang, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital; Zhejiang University School of Medicine; Hangzhou, Zhejiang China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D001343:Autophagy / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D008247:Lysosomes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
keywords: autophagy; hepatitis B virus; hepatitis B virus X protein; hepatocellular carcinoma; lysosome