Np95/ICBP90-like RING finger protein (NIRF), a novel E3 ubiquitin ligase, has been shown to interact with HBc and promote its degradation. This study investigated the effects of NIRF on replication of hepatitis B virus (HBV) and the mechanisms. We have shown that NIRF inhibits replication of HBV DNA and secretion of HBsAg and HBeAg in HepG2 cells transfected with pAAV-HBV1.3. NIRF also inhibits the replication and secretion of HBV in a mouse model that expressed HBV. NIRF reduces acetylation of HBV cccDNA-bound H3 histones. These results showed that NIRF is involved in the HBV replication cycle not only through direct interaction with HBc but also reduces acetylation of HBV cccDNA-bound H3 histones.
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References
1.
BronnerC., AchourM., ArimaY., ChataigneauT., SayaH., and Schini-KerthV.B. (2007). The UHRF family: oncogenes that are drugable targets for cancer therapy in the near future. Pharmacol Ther, 115, 419–434.
2.
ChisariF.V. (2000). Viruses, immunity, and cancer: lessons from hepatitis B. Am J Pathol, 156, 1117–1132.
3.
GerleB., KoroknaiA., FejerG., BakosA., BanatiF., SzentheK., WolfH., NillerH.H., MinarovitsJ., and Salamon. (2007). Acetylated histone H3 and H4 mark the upregulated LMP2A promoter of Epstein–Barr virus in lymphoid cells. J Virol, 81, 13242–13247.
4.
JacksonP.K., EldridgeA.G., FreedE., FurstenthalL., HsuJ.Y., KaiserB.K., and ReimannJ.D. (2000). The lore of the RINGs-substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol, 10, 429–439.
5.
JeongH., ChoM.H., ParkS.G., and JungG. (2014). Interaction between nucleophosmin and HBV core protein increases HBV capsid assembly. FEBS Lett, 588, 851–858.
6.
KangH., YuJ., and JungG. (2008). Phosphorylation of hepatitis B virus core Cterminally truncated protein (Cp149) by PKC increases capsid assembly andstability. Biochem J, 416, 47–54.
7.
LeeS.J., ShimH.Y., HsiehA., MinJ.Y., and JungG. (2009). Hepatitis B virus core interacts with the host cell nucleolar protein, nucleophosmin 1. J Microbiol, 47, 746–752.
8.
LiuF., SongY., and LiuD. (1999). Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther, 6, 1258–1266.
9.
MoollaN., KewM., and ArbuthnotP. (2002). Regulatory elements of hepatitis B virus transcription. J Viral Hepat, 9, 323–331.
10.
MoriT., IkedaD.D., FukushimaT., TakenoshitaS., and KochiH. (2011). NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor. Cell Cycle, 10, 3284–3299.
11.
MoriT., IkedaD.D., YoshikiY., UnokiM.; NIRF Project. (2012). NIRF/UHRF2 occupies a central position in the cell cycle network and allows coupling with the epigenetic landscape. FEBS Lett, 586, 1570–1583.
12.
MoriT., LiY., HataH., and KochiH. (2004). NIRF is a ubiquitin ligase that is capable of ubiquitinating PCNP, a PEST-containing nuclear protein. FEBS Lett, 557, 209–214.
13.
MoriT., LiY., HataH., OnoK., and KochiH. (2002). NIRF, a novel RING finger protein, isinvolved in cell-cycle regulation. Biochem Biophys Res Commun, 296, 530–536.
14.
NassalM. (2008). Hepatitis B viruses: reverse transcription a different way. Virus Res, 134, 235–249.
15.
OttJ.J., StevensG.A., GroegerJ., and WiersmaS.T. (2012). Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine, 30, 2212–2219.
16.
PorterfieldJ.Z., DhasonM.S., LoebD.D., NassalM., StrayS.J., and ZlotnickA. (2010). Full-length hepatitis B virus core protein packages viral and heterologous RNA with similarly high levels of cooperativity. J Virol, 84, 7174–7184.
17.
QianG., JinF., ChangL., YangY., PengH., and DuanC. (2012). NIRF, a novel ubiquitin ligase, interacts with hepatitis B virus core protein and promotes its degradation. Biotechnol Lett, 34, 29–36.
18.
ShimH.Y., QuanX., YiY.S, and JungG. (2011). Heat shock protein 90 facilitates formation of the HBV capsid via interacting with the HBV core protein dimers. Virology, 410, 161–169.
19.
TeresaP., LauraB., GiusepeppinaR., NataliaP., GiovanniS., GiovanniR., and MassimoL. (2006). Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology, 130, 823–837.
20.
XuW.S., ZhaoK.K., MiaoX.H., WuN., CaiX., ZhangR.Q., and WanJ. (2010). Effect of oxymatrine on the replication cycle ofhepatitis B virus in vitro. World J Gastroenterol, 16, 2028–2037.
21.
ZhangG., BudkerV., and WolffJ.A. (1999). High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther, 10, 1735–1737.
