Virus Genes

, Volume 52, Issue 5, pp 597–605 | Cite as

Proteasomes regulate hepatitis B virus replication by degradation of viral core-related proteins in a two-step manner

  • Zi-Hua Zheng
  • Hui-Ying Yang
  • Lin Gu
  • Xiao-Mou Peng


The cellular proteasomes presumably inhibit the replication of hepatitis B virus (HBV) due to degradation of the viral core protein (HBcAg). Common proteasome inhibitors, however, either enhance or inhibit HBV replication. In this study, the exact degradation process of HBcAg and its influences on HBV replication were further studied using bioinformatic analysis, protease digestion assays of recombinant HBcAg, and proteasome inhibitor treatments of HBV-producing cell line HepG2.2.15. Besides HBcAg and hepatitis B e antigen precursor, common hepatitis B core-related antigens (HBcrAgs), the small and the large degradation intermediates of these HBcrAgs (HBcrDIs), were regularly found in cytosol of HepG2.2.15 cells. Further, the results of investigation reveal that the degradation process of cytosolic HBcrAgs in proteasomes consists of two steps: the limited proteolysis into HBcrDIs by the trypsin-like (TL) activity and the complete degradation of HBcrDIs by the chymotrypsin-like (chTL) activity. Concordantly, HBcrAgs and the large HBcrDI or HBcrDIs (including the small HBcrDI) were accumulated when the TL or chTL activity was inhibited, which generally correlated with enhancement and inhibition of HBV replication, respectively. The small HBcrDI inhibited HBV replication by assembling into the nucleocapsids and preventing the victim particles from being mature enough for envelopment. The two-step degradation manner may highlight some new anti-HBV strategies.


Hepatitis B virus HBcrAgs Viral replication Protein degradation Proteasomes 


  1. 1.
    D. Ganem, A.M. Prince, N. Engl, J. Med. 350, 1118–1129 (2004)Google Scholar
  2. 2.
    Y.F. Liaw, Liver Int. 29(Suppl 1), 100–107 (2009)CrossRefPubMedGoogle Scholar
  3. 3.
    M. Ait-Goughoulte, J. Lucifora, F. Zoulim, D. Durantel, Viruses 2, 1394–1410 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    G.J. Webster, S. Reignat, M.K. Maini, S.A. Whalley, G.S. Ogg, A. King, D. Brown, P.L. Amlot, R. Williams, D. Vergani, G.M. Dusheiko, A. Bertoletti, Hepatology 32, 1117–1124 (2000)CrossRefPubMedGoogle Scholar
  5. 5.
    A. Bertoletti, A.J. Gehring, J. Gen. Virol. 87, 1439–1449 (2006)CrossRefPubMedGoogle Scholar
  6. 6.
    J. Beck, M. Nassal, World J. Gastroenterol. 13, 48–64 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    M. Biermer, R. Puro, R.J. Schneider, J. Virol. 77, 4033–4042 (2003)CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Y.C. Chou, M.L. Chen, C.P. Hu, Y.L. Chen, C.L. Chong, Y.L. Tsai, T.L. Liu, K.S. Jeng, C. Chang, Hepatology 46, 672–681 (2007)CrossRefPubMedGoogle Scholar
  9. 9.
    S. Braun, A. Zajakina, J. Aleksejeva, A. Sharipo, R. Bruvere, V. Ose, P. Pumpens, H. Garoff, H. Meisel, T. Kozlovska, J. Med. Virol. 79, 1312–1321 (2007)CrossRefPubMedGoogle Scholar
  10. 10.
    S.Y. Sohn, S.B. Kim, J. Kim, B.Y. Ahn, J. Gen. Virol. 87, 1883–1891 (2006)CrossRefPubMedGoogle Scholar
  11. 11.
    Z. Zhang, E. Sun, J.H. Ou, T.J. Liang, J. Virol. 84, 9326–9331 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    P. Bandi, M.L. Garcia, C.J. Booth, F.V. Chisari, M.D. Robek, Agents Chemother. 54, 749–756 (2010)CrossRefGoogle Scholar
  13. 13.
    Y. Zheng, L. Zhao, T. Wu, S. Guo, Y. Chen, T. Zhou, Virol. J 6, 99 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    C. Xu, H. Guo, X.B. Pan, R. Mao, W. Yu, X. Xu, L. Wei, J. Chang, T.M. Block, J.T. Guo, J. Virol. 84, 9332–9340 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    M.D. Robek, S.F. Wieland, F.V. Chisari, J. Virol. 76, 3570–3574 (2002)CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    K. Ito, K.H. Kim, A.S. Lok, S. Tong, J. Virol. 83, 3507–3517 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    M. Duriez, J.M. Rossignol, D. Sitterlin, J. Biol. Chem. 283, 32352–32360 (2008)CrossRefPubMedGoogle Scholar
  18. 18.
    Y.J. Pang, X.J. Tan, D.M. Li, Z.H. Zheng, R.X. Lei, X.M. Peng, Liver Int. 33, 1230–1238 (2013)CrossRefPubMedGoogle Scholar
  19. 19.
    M. Sugiyama, Y. Tanaka, F. Kurbanov, N. Nakayama, S. Mochida, M. Mizokami, Virology 365, 285–291 (2007)CrossRefPubMedGoogle Scholar
  20. 20.
    H.Y. Yang, N.Q. Zheng, D.M. Li, L. Gu, X.M. Peng, Virol. J 11, 165 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    M. Seifer, D.N. Standring, J. Virol. 68, 5548–5555 (1994)PubMedPubMedCentralGoogle Scholar
  22. 22.
    R.A. Moravec, M.A. O’Brien, W.J. Daily, M.A. Scurria, L. Bernad, T.L. Riss, Anal. Biochem. 387, 294–302 (2009)CrossRefPubMedGoogle Scholar
  23. 23.
    P.P. Scaglioni, M. Melegari, J.R. Wands, J. Virol. 71, 345–353 (1997)PubMedPubMedCentralGoogle Scholar
  24. 24.
    T. Jung, B. Catalgol, T. Grune, Mol. Aspects Med. 30, 191–296 (2009)CrossRefPubMedGoogle Scholar
  25. 25.
    I.M.S. Seda, J.L. Mott, Y. Akazawa, F.J. Barreyro, S.F. Bronk, S.H. Kaufmann, G.J. Gores, Hepatol. Res 40, 701–710 (2010)CrossRefGoogle Scholar
  26. 26.
    B. Pandit, A.L. Gartel, Am. J. Pathol. 178, 355–360 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    K.A. Rodriguez, M. Gaczynska, P.A. Osmulski, Mech. Ageing Dev. 131, 144–155 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    T. Hayashi, S. Goto, Mech. Ageing Dev. 102, 55–66 (1998)CrossRefPubMedGoogle Scholar
  29. 29.
    Z. Hu, Z. Zhang, E. Doo, O. Coux, A.L. Goldberg, T.J. Liang, J. Virol. 73, 7231–7240 (1999)PubMedPubMedCentralGoogle Scholar
  30. 30.
    J.B. Sunwoo, Z. Chen, G. Dong, N. Yeh, C.C. Bancroft, E. Sausville, J. Adams, P. Elliott, C. Van Waes, Clin. Cancer Res 7, 1419–1428 (2001)PubMedGoogle Scholar
  31. 31.
    J. Jung, H.Y. Kim, T. Kim, B.H. Shin, G.S. Park, S. Park, Y.J. Chwae, H.J. Shin, K. Kim, PLoS One 7, e41087 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    J. Köck, M. Nassal, K. Deres, H.E. Blum, F. von Weizsäcker, J. Virol. 78, 13812–13818 (2004)CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Zi-Hua Zheng
    • 1
    • 2
    • 3
  • Hui-Ying Yang
    • 1
    • 2
  • Lin Gu
    • 4
  • Xiao-Mou Peng
    • 1
    • 4
  1. 1.Hepatology Laboratory, The Hospital for Liver DiseaseSun Yat-Sen UniversityGuangzhouChina
  2. 2.Department of Infectious Diseases, The Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina
  3. 3.Jinan University Clinic, The First Affiliated HospitalJinan UniversityGuangzhouChina
  4. 4.Liver Disease Key Laboratory of Guangdong ProvinceGuangzhouChina

Personalised recommendations