Mechanisms and Effects on HBV Replication of the Interaction between HBV Core Protein and Cellular Filamin B
Hepatitis B virus (HBV) infection is one of the major problems that threatens global health. There have been many studies on HBV, but the relationship between HBV and host factors is largely unexplored and more studies are needed to clarify these interactions. Filamin B is an actin-binding protein that acts as a cytoskeleton protein, and it is involved in cell development and several signaling pathways. In this study, we showed that filamin B interacted with HBV core protein, and the interaction promoted HBV replication. The interaction between filamin B and core protein was observed in HEK 293T, Huh7 and HepG2 cell lines by co-immunoprecipitation and co-localization immnofluoresence. Overexpression of filamin B increased the levels of HBV total RNAs and pre-genome RNA (pgRNA), and improved the secretion level of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). In contrast, filamin B knockdown inhibited HBV replication, decreased the level of HBV total RNAs and pgRNA, and reduced the secretion level of HBsAg and HBeAg. In addition, we found that filamin B and core protein may interact with each other via four blocks of argentine residues at the C-terminus of core protein. In conclusion, we identify filamin B as a novel host factor that can interact with core protein to promote HBV replication in hepatocytes. Our study provides new insights into the relationship between HBV and host factors and may provide new strategies for the treatment of HBV infection.
KeywordsFilamin B Core HBV replication
We thank Prof. Arnoud Sonnenberg (Division of Cell Biology, Netherlands Cancer Institute) for his kind gift of the plasmid Filamin B -GFP. We would also like to thank Prof. Xinwen Chen (State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China) for his kind gift of the plasmid Core -HA. This research was supported by the Postdoctoral Science Foundation of China.
JFM, DYG and LC conceived the study and participated in the design. YLL and YSS performed the experiments and drafted the manuscript. FYS, RH and CLL analyzed data. JFM and DYG finalized the manuscript. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Animal and Human Rights Statement
This article does not contain any studies with human or animal subjects performed by any of the authors.
- Bicknell LS, Farrington-Rock C, Shafeghati Y, Rump P, Alanay Y, Alembik Y, Al-Madani N, Firth H, Karimi-Nejad MH, Kim CA, Leask K, Maisenbacher M, Moran E, Pappas JG, Prontera P, de Ravel T, Fryns JP, Sweeney E, Fryer A, Unger S, Wilson LC, Lachman RS, Rimoin DL, Cohn DH, Krakow D, Robertson SP (2007) A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet 44:89–98CrossRefPubMedGoogle Scholar
- Brocker F, Bardenheuer W, Vieten L, Julicher K, Werner N, Marquitan G, Michael D, Opalka B, Schutte J (1999) Assignment of human filamin gene FLNB to human chromosome band 3p14.3 and identification of YACs containing the complete FLNB transcribed region. Cytogenet Cell Genet 85:267–268CrossRefPubMedGoogle Scholar
- Cooper J, Liu L, Woodruff EA, Taylor HE, Goodwin JS, D’Aquila RT, Spearman P, Hildreth JE, Dong X (2011) Filamin A protein interacts with human immunodeficiency virus type 1 Gag protein and contributes to productive particle assembly. J Biol Chem 286:28498–28510CrossRefPubMedPubMedCentralGoogle Scholar
- del Valle-Perez B, Martinez VG, Lacasa-Salavert C, Figueras A, Shapiro SS, Takafuta T, Casanovas O, Capella G, Ventura F, Vinals F (2010) Filamin B plays a key role in vascular endothelial growth factor-induced endothelial cell motility through its interaction with Rac-1 and Vav-2. J Biol Chem 285:10748–10760CrossRefPubMedPubMedCentralGoogle Scholar
- Jung J, Hwang SG, Chwae YJ, Park S, Shin HJ, Kim K (2014) Phosphoacceptors threonine 162 and serines 170 and 178 within the carboxyl-terminal RRRS/T motif of the hepatitis B virus core protein make multiple contributions to hepatitis B virus replication. J Virol 88:8754–8767CrossRefPubMedPubMedCentralGoogle Scholar
- Klumpp K, Shimada T, Allweiss L, Volz T, Lutgehetmann M, Hartman G, Flores OA, Lam AM, Dandri M (2017) Efficacy of NVR 3-778, alone and in combination with pegylated interferon, vs entecavir in uPA/SCID mice with humanized livers and HBV infection. Gastroenterology. https://doi.org/10.1053/j.gastro.2017.10.017 PubMedGoogle Scholar
- Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, Wachsmann-Hogiu S, Acuna D, Shapiro SS, Takafuta T, Aftimos S, Kim CA, Firth H, Steiner CE, Cormier-Daire V, Superti-Furga A, Bonafe L, Graham JM Jr, Grix A, Bacino CA, Allanson J, Bialer MG, Lachman RS, Rimoin DL, Cohn DH (2004) Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 36:405–410CrossRefPubMedGoogle Scholar
- van der Flier A, Kuikman I, Kramer D, Geerts D, Kreft M, Takafuta T, Shapiro SS, Sonnenberg A (2002) Different splice variants of filamin-B affect myogenesis, subcellular distribution, and determine binding to integrin [beta] subunits. J cell Biol 156:361–376CrossRefPubMedPubMedCentralGoogle Scholar
- Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1:e00049CrossRefPubMedPubMedCentralGoogle Scholar