title: Hepatitis B virus-triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response.
abstract: Death receptors of TNFSF10/TRAIL (tumor necrosis factor superfamily member 10) contribute to immune surveillance against virus-infected or transformed cells by promoting apoptosis. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling, leading to persistent infection. Here, we report that hepatitis B virus (HBV) X protein (HBx) restricts TNFSF10 receptor signaling via macroautophagy/autophagy-mediated degradation of TNFRSF10B/DR5, a TNFSF10 death receptor, and thus permits survival of virus-infected cells. We demonstrate that the expression of the TNFRSF10B protein is dramatically reduced both in liver tissues of chronic hepatitis B patients and in cell lines transfected with HBV or HBx. HBx-mediated downregulation of TNFRSF10B is caused by the lysosomal, but not proteasomal, degradation pathway. Immunoblotting analysis of LC3B and SQSTM1, and microscopy analysis of tandem-fluorescence-tagged LC3B revealed that HBx promotes complete autophagy. Inhibition of autophagy with a pharmacological inhibitor and LC3B knockdown revealed that HBx-induced autophagy is crucial for TNFRSF10B degradation. Immunoprecipitation and GST affinity isolation assays showed that HBx directly interacts with TNFRSF10B and recruits it to phagophores, the precursors to autophagosomes. We confirmed that autophagy activation is related to the downregulation of the TNFRSF10B protein in liver tissues of chronic hepatitis B patients. Inhibition of autophagy enhanced the susceptibility of HBx-infected hepatocytes to TNFSF10. These results identify the dual function of HBx in TNFRSF10B degradation: HBx plays a role as an autophagy receptor-like molecule, which promotes the association of TNFRSF10B with LC3B; HBx is also an autophagy inducer. Our data suggest a molecular mechanism for HBV evasion from TNFSF10-mediated antiviral immunity, which may contribute to chronic HBV infection.
authors.affiliation: a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.|b KU Open Innovation Center, Research Institute of Medical Sciences, Konkuk University , Seoul , Korea.
authors.forename: Gu-Choul
authors.initials: GC
authors.lastname: Shin
authors.affiliation: a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Kang
authors.affiliation: a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.
authors.forename: Ah Ram
authors.initials: AR
authors.lastname: Lee
authors.affiliation: a Department of Pharmacology , Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University , Seoul , Korea.|b KU Open Innovation Center, Research Institute of Medical Sciences, Konkuk University , Seoul , Korea.|c Research Institute of Medical Sciences, Konkuk University , Seoul , Korea.
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
mesh_terms: D001343:Autophagy; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000378:metabolism*; D006521:Hepatitis, Chronic / Q000235:genetics / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D046988:Proteasome Endopeptidase Complex
keywords: HBx; Hepatitis B virus; TNFSF10/TRAIL; autophagy; immune evasion