Hepatitis B Virus X Protein Sensitizes TRAIL-Induced Hepatocyte Apoptosis by Inhibiting the E3 Ubiquitin Ligase A20

Abstract

Hepatitis B virus (HBV) infection causes hepatocyte death and liver damage, which may eventually lead to cirrhosis and liver cancer. Hepatitis B virus X protein (HBx) is a key antigen that is critically involved in HBV-associated liver diseases. However, the molecular basis for its pathogenesis, particularly in liver damage, has not been well defined. Herein, we report that HBx was able to enhance the susceptibility of hepatocytes to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Increased sensitivity to TRAIL was associated with HBx-induced upregulation of miR-125a, which, in turn, suppressed the expression of its putative target gene, A20 E3 ligase. Importantly, we demonstrate that the defective expression of A20 impaired the K63-linked polyubiquitination of caspase-8, which reciprocally enhanced the activation of caspase-8, the recruitment of Fas-associated death domain (FADD), and the formation of death-inducing signaling complex (DISC), thereby promoting HBx-mediated apoptotic signaling. Accordingly, antagonizing miR-125a or ectopically expressing A20 in hepatocytes abolished the pro-apoptotic effect of HBx. Conversely, the overexpression of miR-125a or knockdown of A20 mimicked HBx to enhance TRAIL susceptibility in hepatocytes. Thus, we establish, for the first time, a miR-125a/A20-initiated and caspase-8-targeted mechanism by which HBx modulates apoptotic signaling and increases hepatic susceptibility to the damaging agent, which might provide novel insight into HBV-related liver pathology.

DR5‐Cbl‐b/c‐Cbl‐TRAF2 complex inhibits TRAIL‐induced apoptosis by promoting TRAF2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells

“…Our present data showed that in TRAIL‐sensitive cells, Cbl‐b and c‐Cbl, the critical adaptors linking DR5 and TRAF2, were expressed at a low level. Previous studies reported that the hepatitis B virus X protein enhanced the sensitivity of hepatocytes to TRAIL by upregulation of miR‐125a targeting TNFAIP3 to enhance the activation of caspase‐8 (Zhang et al ., 2015b). Because our present data showed no changes in Cbl‐b and c‐Cbl mRNA in TRAIL‐sensitive and TRAIL‐resistant gastric cancer cells, we performed Affymetrix miRNA chip analyses to identify potential miRNA.…”

Association of the tandem polymorphisms (rs148314165, rs200820567) in TNFAIP3 with chronic hepatitis B virus infection in Chinese Han population

“…Alterations of A20 may affect the progress of HBV infection and liver diseases. For instance, HBV X protein (HBx) was indicated to be able to affect the expression of A20 and promote TNF-related apoptosis-inducing ligand (TRAIL)-induced hepatocyte apoptosis [ 11 ]. A20 mRNA expression in peripheral blood mononuclear cells was shown to be associated with progression of chronic HBV infection [ 12 ], and increased A20 expression on monocytes was shown to be associated with the severity of acute-on-chronic liver failure related to HBV infection [ 13 ].…”

Up‐regulation of A20 gene expression in peripheral blood mononuclear cells is associated with acute‐on‐chronic hepatitis B liver failure

“…Zhang et al . showed that hepatitis B virus X protein (HBx) sensitizes TNF‐related apoptosis‐inducing ligand (TRAIL)‐induced hepatocyte apoptosis by inhibiting A20 at the protein but not the mRNA level via upregulation of miR‐125a. Thus, further research is necessary to elucidate whether HBV proteins have any impact upon the expression of A20 protein.…”