Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant

Abstract

AIM:To investigate the mechanism of endoplasmic reticulum (ER) stress induction by an occult infection related hepatitis B virus S surface antigen (HBsAg) variant. METHODS:We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot. RESULTS:Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species (ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins (HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins (caspase 6, 9 and 12). Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein. CONCLUSION:Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.

Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma

“…ER stress caused the release of calcium from the ER to the cytoplasm, which induced intracellular reactive oxygen species (ROS). Interestingly, we also found that the expression of antioxidant proteins such as superoxide dismutase (MnSOD and CuZnSOD), HO-1, and catalase were substantially reduced in the KD variant [18]. These data strongly implied the pathway of ER stress-linked ROS generation [78].…”

“…In our previous study, we introduced a total of 10 types of HBsAg variants from a Korean occult cohort that could be divided into five groups according to intracellular and secretion levels of HBsAg and virions [77]. In our further study of these variants, we investigated an occult infection-related HBsAg variant (KD variant with five mutations: W36L, T47K, N52D, V184A, and F220L), which belonged to group II and showed a high level of intracellular HBsAg due to an almost negative secretion capacity [18].…”

eNOS/iNOS and endoplasmic reticulum stress-induced apoptosis in the placentas of patients with preeclampsia

“…35 It has been reported that the HBsAg variant activates ER-related genes and induces ER stress that mediates the induction of reactive oxygen species, NO and apoptosis in similar manners. 36 In addition, the PERK pathway is involved in NO-induced apoptosis in endothelial cells under high-glucose conditions. 37 Moreover, NO-induced apoptosis in pancreatic β-cells is mediated by the ER stress pathway.…”

Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner

“…Meanwhile, during chronic HBV infection, the integration of viral DNA into the host chromosome may cause viral genomic disruptions and then induce a dysregulation of surface protein production, which in turn leads to the overexpression of LHBs and the accumulation of MHBs and SHBs in the ER [ 6 , 11 ]. The aggregation of mutant HBV surface antigen variants were reported to cause ER stress [ 4 , 33 ]. Persistent ER stress activates autophagy, which is beneficial for hepatocyte survival and viral persistence.…”