title: Hepatitis B virus encoded X protein suppresses apoptosis by inhibition of the caspase-independent pathway.
abstract: Hepatitis B virus (HBV) encoded X protein (HBx) has been implicated in apoptotic and related pathogenic events during hepatocellular carcinoma. However, the underlying molecular mechanism through which HBx acts is largely unclear. We used tandem affinity purification under mild conditions to gain insight into the HBx interactome in HBV-producing HepG2.2.15 cells and identified 49 proteins by mass spectrometry that are potentially associated with HBx. Two of the key proteins of the caspase-independent apoptosis pathway were newly identified, apoptosis-inducing factor (AIF) and the homologous AMID (AIF-homologue mitochondrion-associated inducer of death). We confirmed the interactions of HBx with AIF and with AMID by reciprocal coimmunoprecipitation experiments, respectively. We observed the expression of HBx-reduced AIF-mediated apoptosis and HBx colocalization with AIF and AMID, principally in the cytoplasm. Furthermore, the elevated cytoplasmic levels of HBx could inhibit mitochondrion-to-nucleus translocation of AIF. Here, we present the first detailed molecular evidence that HBx can repress apoptosis via inhibition of the caspase-independent apoptosis pathway. This inhibition of apoptosis involves the repression of the mitochondrion-to-nucleus translocation of AIF, although tests with AMID were not conclusive. These findings provide important insights into the new mechanism of the apoptosis inhibition by HBV.
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Yuan
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.forename: Keith
authors.initials: K
authors.lastname: Mitchelson
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Wenyan
authors.initials: W
authors.lastname: Qin
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000302:isolation & purification / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000302:isolation & purification / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002846:Chromatography, Affinity; D056945:Hep G2 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D024101:Mitochondrial Proteins / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C494829:AIFM1 protein, human; C462504:ferroptosis suppressor protein 1, human; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D020169:Caspases