Endoplasmic reticulum stress induced by hepatitis B virus X protein enhances cyclo-oxygenase 2 expression via activating transcription factor 4

Abstract

Chronic hepatitis B is a disease of the liver that can progress to cirrhosis and liver cancer. The HBx (hepatitis B virus X) protein of hepatitis B virus is a multifunctional regulator that induces ER (endoplasmic reticulum) stress by previously unknown mechanisms. ER stress plays a critical role in inflammatory induction and COX2 (cyclo-oxygenase 2) is an important mediator of this inflammation. In the present study, we demonstrate the molecular mechanisms of HBx on induction of ER stress and COX2 expression. In addition, HBx reduced expression of enzymes which are involved in mitochondrial β-oxidation of fatty acids and the mitochondrial inner membrane potential. The reduction in intracellular ATP levels by HBx induced the unfolded protein response and COX2 expression through the eIF2α (eukaryotic initiation factor 2α)/ATF4 (activating transcription factor 4) pathway. We confirmed that ATF4 binding to the COX2 promoter plays a critical role in HBx-mediated COX2 induction. The results of the present study suggest that HBV infection contributes to induction of hepatic inflammation through dysfunction of cellular organelles including the ER and mitochondria.

ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

“…In this study, we provided evidence that ATF4 is directly induced by TLR4 signaling instead of via ER stress ( Supplementary Figure 9c and 10). Many viruses, such as human cytomegalovirus, 31 herpesvirus, 32 HCV 33 and HBV, 34 have also been shown to stimulate ATF4 production via the ER stress response. The lentivirus infection system that we used in the experiment is only sustained for 1 h, and a scramble control was included, which have been used in many other studies.…”

Hepatitis B virus X increases immune cell recruitment by induction of chemokine SDF‐1

“…Therefore, based on our previous finding that HBx induces ER stress [16], we investigated whether or not HBx-induced SDF-1 expression is related to ER stress. As shown in Fig.…”

“…Lee (Chungbuk National University, Korea). pcDNA3-HBx, pcDNA3-HBV 1.2mer, pcDNA3-HBV(-x) 1.2mer, pCMV5-myc-ATF4 and pcDNA-HA-CREBH(n) were described previously [16]. pcDNA3-HA-ATF6a(n), pcDNA3-flag-XBP1(s) and pAdTrack-CMV were kindly gifted from Dr. K.H.…”

“…PCR was carried out using the following forward and reverse primers: SDF-1 F, 5 0 -GCC AGA GCC AAC GTC AAG CAT-3 0 ; SDF-1 R, 5 0 -CTT GTT TAA AGC TTT CTC CAG GTA CTC-3 0 . The primers of actin, BIP, HBx, and XBP1 were described previously [16]. The number of wild type and HBx-TG used in RT-PCR was twelve mice, respectively.…”

Enhanced autophagic flux by endoplasmic reticulum stress in human hepatocellular carcinoma cells contributes to the maintenance of cell viability

“…In HCC, a number of environmental factors such as hypoxia, viral (16)(17)(18)(19)(20)(21). Moreover, ER stress is involved in several signal pathways related to hepatocellular proliferation, survival and apoptosis (22)(23)(24). ER stress and autophagy in HCC often share the same stimuli (10,18,21,25,26).…”