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/autophagymediated degradation of TNFRSF10B/DR5, a TNFSF10 death receptor, and thus permits survival of virusinfected 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.

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

“…In line with this hypothesis, knockdown of LC3B led to a~40% reduction of Tginduced cell death and a~30% reduction of Tg-induced PARP cleavage in LNCaP cells ( Fig Combined silencing of LC3A and LC3B did not produce any further reduction in Tg-induced cell death compared to that observed upon silencing of LC3B alone (data not shown). Hepatitis B virus-induced autophagy can trigger LC3B-dependent degradation of DR5 [66]. However, and in accordance with Tg blocking functional autophagy [33], knockdown of LC3B did not result in higher DR5 protein levels in Tg-treated cells (Additional file 2: Figure S7, C-F).…”

Cell Death and Liver Disease

“…17 HBx also promotes autophagic and lysosomal degradation of the TNFSF10/TRAIL (tumor necrosis factor related apoptosis-inducing ligand) death receptors, supporting survival of HBV-infected cells and evading antiviral immunity. 18 In fact, HBx stimulates Parkin-mediated mitophagy and suppresses mitochondrial apoptosis, a mechanism which may contribute to HBV-induced hepatocarcionogenesis. 19…”

Alteration of microRNA profiles by a novel inhibitor of human La protein in HBV‐transformed human hepatoma cells

“…CCND2 regulated HBV replication via enhancing the acivity of HBV core promoters . TNFSF10 has been reported to paticipate in HBV evasion through HBX‐induced autophagy . SUZ12 was activated during both HBV replication and liver carcinogenesis .…”