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

Abstract

Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation via enhanced inflammation, oxidative stress-mediated DNA damage, and hepatocyte proliferation. In the natural course of HBV infection, the accumulation of naturally occurring mutations in the HBV genome can generate several mutant types of HBV-encoded proteins, including three different proteins in the S ORF (SHBs, MHBs, and LHBs) and HBcAg in the C ORF, which could contribute to enhanced ER stress in infected hepatocytes mainly via increased ER accumulation of mutant proteins. However, it seems that there may be distinct capacity and pathway in ER stress-induction and distinct resulting clinical outcomes between HBV variants. In addition, the role of HBxAg mutations in ER stress remains unknown. However, it has been reported that HBxAg itself could exert ER stress in infected cells, resulting in HCC generation in chronic HBV patients. To date, review papers regarding ER stress-mediated HBV mutation have been limited into a specific mutation type: preS2 deletion. So, in this review, we will discuss details about various mutation types in all four regions of the HBV genome (preS1, preS2, S, and C) related to ER stress and their distinct ER stress mechanisms and clinical outcomes in terms of mutation types.

Keywords: ATF6; Endoplasmic Reticulum stress; HBV surface antigen (HBsAg); HBx mutations; Hepatitis B virus infection (HBV); Hepatocellular carcinoma (HCC), apoptosis; IRE1; PERK; Unfolded protein response (UPR); core mutations; preS/S mutations.

Figure 1

Locations and types of hepatitis B virus (HBV) mutations reported to induce endoplasmic reticulum (ER) stress in previous literature. Mutations in preS1 ([11,13,14,15]), and PreS2 ([11,13,16,17]) deletion in PreS1 and preS2 ([13,15,16,17]), or deletion in both region ([16]) are indicated. Several mutations in S regions are reported ([16,18,19]) including those in "a" determinant ([20]). Mutations in core ([21]) and X region ([22,23,24]) reported to cause ER stress are indicated.

Figure 2

Schematic pathway for ER stress-mediated HCC generation caused by several types of HBV variants such as preS/S, core mutants, and HBx proteins. Naturally occurring mutant HBV proteins, which are caused by immune pressure during chronic HBV infection, including HBsAg, MHBs, LHBs, and HBcAg, could accumulate in the ER and induce ER stress. The HBsAg, MHBs, and LHBs variants could lead to defective HBsAg secretion due to disturbance of the ratio between LHBs and HBsAg. Meanwhile, HBcAg variants could increase the capacity of HBsAg secretion, which may be due to activation of the S promoter via ER stress, and induced ER stress could activate three different UPR transducers: PERK, IRE1, and ATF6. Generally, ER stress-mediated UPRs could contribute to HCC generation in chronic HBV patients via distinct biological actions including ROS production, inflammation, apoptosis, and the activation of NF-κB. Black arrows indicate positive regulation. T-bars indicate suppression. The red arrow implies an unknown consequence of ER stress yet via HBV genome mutation for the progression of HCC. HBsAg, hepatitis B virus surface antigen; MHBs, hepatitis B middle surface protein; LHBs, hepatitis B large surface proteins; HBcAg, hepatitis B core antigen.