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Review
. 2017 Aug 18;9(8):230.
doi: 10.3390/v9080230.

Interference of Apoptosis by Hepatitis B Virus

Shaoli Lin  1 , Yan-Jin Zhang  2
Affiliations
Review

Interference of Apoptosis by Hepatitis B Virus

Shaoli Lin et al. Viruses. .

Abstract

Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective.

Keywords: X protein; apoptosis; hepatitis B virus (HBV); hepatocellular carcinoma (HCC).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Inhibition of apoptosis by hepatitis B Virus (HBV) infection. Hepatitis B Virus X protein (HBX) and HBV core inhibit p53-mediated apoptosis. HBX activates the phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B (PI3K-Akt) pathway to inhibit apoptosis via the upregulation of PI3K and the induction of Akt phosphorylation. HBX inhibits the intrinsic apoptotic pathway by recruitment of Drp-1 and Parkin to the mitochondria for mitochondrial fission and mitophagy. The activation of Akt also prevents translocation of BAD to the mitochondria, thereby preventing apoptosis. HBX can activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling via the degradation of IκB. In the MAPK-JNK pathway, HBV can attenuate the function of the kinase that activates JNK. HBV can downregulate apoptosis by either elevation of anti-apoptotic ncRNAs such as MiR-181a, or decrease of pro-apoptotic ncRNAs, such as MiR-29c. Green arrows next to the white boxes (HBV or HBV proteins) denote the activation of apoptosis. Red bars to the white boxes stand for the inhibition of apoptosis. Drp-1: Dynamin-1-like protein. BAD: BCL-2-associated death promoter. MAPK: MAP kinase. JNK: c-Jun N-terminal kinases. ncRNA: Non-coding RNA. MiR-181a/29c: MicroRNA 181a/29c.
Figure 2
Figure 2
Pro-apoptotic role of HBV. HBV infection causes the activation of NF-κB in hepatoma cells, and subsequent excessive expression of the death-associated receptors, which increase the cell sensitivity to stimuli. In addition, HBV directly induces the cleavage of caspase 3 to activate apoptosis. HBV induces the mitochondrial apoptotic signaling pathway by increasing the BAX expression and the ROS level or downregulating Mcl-1. The BCL-2 homology domain 3 (BH3)-like domain in HBX also plays a role in the induction of apoptosis. Green arrows mean the activation step of apoptosis; Red bars stand for the inhibition step of apoptosis.
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