Hepatitis B virus X protein is capable of down-regulating protein level of host antiviral protein APOBEC3G

Abstract

The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family proteins bind RNA and single-stranded DNA, and create C-to-U base modifications through cytidine deaminase activity. APOBEC3G restricts human immunodeficiency virus 1 (HIV-1) infection by creating hypermutations in proviral DNA, while HIV-1-encoded vif protein antagonizes such restriction by targeting APOBEC3G for degradation. APOBEC3G also inhibits hepatitis B virus (HBV): APOBEC3G co-expression inhibits HBV replication and evidences exist indicating APOBEC3G-mediated HBV hypermutations in patients. HBV encodes a small non-structural X protein (HBx) with a recognized activating effect on HBV life cycle. In this work, we report the discovery that HBx selectively and dose-dependently decreases the protein level of co-expressed APOBEC3G in transfected Huh-7 cells. The effect was shown to take place post-translationally, but does not rely on protein degradation via proteasome or lysosome. Further work demonstrated that intracellular APOBEC3G is normally exported via exosome secretion and inhibition of exosome biogenesis causes retention of intracellular APOBEC3G. Finally, HBx co-expression specifically enhanced externalization of APOBEC3G via exosomes, resulting in decrease of intracellular APOBEC3G protein level. These data suggest the possibility that in addition to other mechanisms, HBx-mediated activation of HBV might also involve antagonizing of intracellular restriction factor APOBEC3G through promotion of its export.

Exosomal Interferon‐Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti–Hepatitis B Virus Efficacy of Exogenous Interferon Alpha

“…This approach helped to trigger a type I IFN response in uninfected cells, suppressing virus and restricting infection . Moreover, in HBV infection models, antiviral protein apolipoprotein B mRNA‐editing enzyme catalytic polypeptide 1‐like 3G could be exported to neighboring cells by exosomes . Increasing numbers of component proteins in exosomes were screened as biomarkers to assess the host immune microenvironment and improve personalized medicine .…”

“…(29) Moreover, in HBV infection models, antiviral protein apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1-like 3G could be exported to neighboring cells by exosomes. (30) Increasing numbers of component proteins in exosomes were screened as biomarkers to assess the host immune microenvironment and improve personalized medicine. (11) Sharing highly conserved transmembrane structure with IFITM2, IFITM1 and IFITM3 have been reported to be transferred between cells by exosomes.…”

Asymmetric Modification of Hepatitis B Virus (HBV) Genomes by an Endogenous Cytidine Deaminase inside HBV Cores Informs a Model of Reverse Transcription

“…This could explain why HBV has no Vif-like protein to counteract the deaminases. However, it should be noted that X protein was recently shown to downregulate APOBEC3G when coexpressed, while being ineffective against other deaminases (58).…”

The curious case of APOBEC3 activation by cancer-associated human papillomaviruses

“…The human immunodeficiency virus 1 (HIV1) Viral infectivity factor (Vif) protein targets A3 family members for degradation, and the HIV2 Viral protein X (Vpx) protein targets A3A for degradation [ 4 , 5 ]. The Hepatitis B Virus X protein impairs this pathway by packaging A3G into exosomes [ 6 ]. Human polyomaviruses—including the Merkel Cell Polyomavirus (McPyV)—trigger A3 activity, yet McPyV-positive Merkel cell carcinomas do not show an A3 mutational signature [ 7 , 8 ].…”