Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Novel functions of viral anti-apoptotic factors

Abstract

Cellular apoptosis is of major importance in the struggle between virus and host. Although many viruses use various strategies to control the cell death machinery by encoding anti-apoptotic virulence factors, it is now becoming clear that, in addition to their role in inhibiting apoptosis, these factors function in multiple immune and metabolic pathways to promote fitness and pathogenesis. In this Progress article, we discuss novel functions of viral anti-apoptotic factors in the regulation of autophagy, in the nuclear factor-κB (NF-κB) pathway and in interferon signalling, with a focus on persistent and oncogenic gammaherpesviruses. If viral anti-apoptotic proteins are to be properly exploited as targets for antiviral drugs, their diverse and complex roles should be considered.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Viral anti-apoptotic factors target autophagy.
Figure 2: Interference with the NF-κB and IFN pathways by viral anti-apoptotic factors.

Similar content being viewed by others

References

  1. Ferri, K. F. & Kroemer, G. Organelle-specific initiation of cell death pathways. Nature Cell Biol. 3, E255–E263 (2001).

    Article  CAS  Google Scholar 

  2. Fuentes-Gonzalez, A. M., Contreras-Paredes, A., Manzo-Merino, J. & Lizano, M. The modulation of apoptosis by oncogenic viruses. Virol. J. 10, 182 (2013).

    Article  CAS  Google Scholar 

  3. Yang, Z. & Klionsky, D. J. Mammalian autophagy: core molecular machinery and signalling regulation. Curr. Opin. Cell Biol. 22, 124–131 (2010).

    Article  CAS  Google Scholar 

  4. Virgin, H. W. & Levine, B. Autophagy genes in immunity. Nature Immunol. 10, 461–470 (2009).

    Article  CAS  Google Scholar 

  5. Orvedahl, A. & Levine, B. Autophagy in mammalian antiviral immunity. Curr. Top. Microbiol. Immunol. 335, 267–285 (2009).

    CAS  PubMed  Google Scholar 

  6. Liang, C., Lee, J. S. & Jung, J. U. Immune evasion in Kaposi's sarcoma-associated herpes virus associated oncogenesis. Semin. Cancer Biol. 18, 423–436 (2008).

    Article  CAS  Google Scholar 

  7. Sodhi, A. et al. The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10, 133–143 (2006).

    Article  CAS  Google Scholar 

  8. Bhatt, A. P. & Damania, B. AKTivation of PI3K/AKT/mTOR signalling pathway by KSHV. Front. Immunol. 3, 401–417 (2012).

    PubMed  Google Scholar 

  9. Esclatine, A., Chaumorcel, M. & Codogno, P. Macroautophagy signalling and regulation. Curr. Top. Microbiol. Immunol. 335, 33–70 (2009).

    CAS  PubMed  Google Scholar 

  10. Chang, H. H. & Ganem, D. A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 13, 429–440 (2013).

    Article  CAS  Google Scholar 

  11. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    Article  CAS  Google Scholar 

  12. Cuconati, A. & White, E. Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev. 16, 2465–2478 (2002).

    Article  CAS  Google Scholar 

  13. Tarakanova, V. L., Kreisel, F., White, D. W. & Virgin, H. W. 4th. Murine gammaherpesvirus 68 genes both induce and suppress lymphoproliferative disease. J. Virol. 82, 1034–1039 (2008).

    Article  CAS  Google Scholar 

  14. Loh, J. et al. A surface groove essential for viral Bcl-2 function during chronic infection in vivo. PLoS Pathog. 1, e10 (2005).

    Article  Google Scholar 

  15. Ku, B. et al. Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68. PLoS Pathog. 4, e25 (2008).

    Article  Google Scholar 

  16. Xiaofei, E. et al. Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLoS Pathog. 5, e1000609 (2009).

    Article  Google Scholar 

  17. Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    Article  CAS  Google Scholar 

  18. Piya, S. et al. The E1B19K oncoprotein complexes with Beclin 1 to regulate autophagy in adenovirus-infected cells. PLoS ONE 6, e29467 (2011).

    Article  CAS  Google Scholar 

  19. Chugh, P. et al. Constitutive NF-κB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice. Proc. Natl Acad. Sci. USA 102, 12885–12890 (2005).

    Article  CAS  Google Scholar 

  20. Lee, J. S. et al. FLIP-mediated autophagy regulation in cell death control. Nature Cell Biol. 11, 1355–1362 (2009).

    Article  CAS  Google Scholar 

  21. Wang, H. W., Sharp, T. V., Koumi, A., Koentges, G. & Boshoff, C. Characterization of an anti-apoptotic glycoprotein encoded by Kaposi's sarcoma-associated herpesvirus which resembles a spliced variant of human survivin. EMBO J. 21, 2602–2615 (2002).

    Article  CAS  Google Scholar 

  22. Liang, Q. et al. Kaposi's sarcoma-associated herpesvirus K7 modulates Rubicon-mediated inhibition of autophagosome maturation. J. Virol. 87, 12499–12503 (2013).

    Article  CAS  Google Scholar 

  23. Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nature Cell Biol. 11, 468–476 (2009).

    Article  CAS  Google Scholar 

  24. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    Article  CAS  Google Scholar 

  25. Sun, S. C. & Cesarman, E. NF-κB as a target for oncogenic viruses. Curr. Top. Microbiol. Immunol. 349, 197–244 (2011).

    CAS  PubMed  Google Scholar 

  26. Sun, Q., Matta, H. & Chaudhary, P. M. The human herpes virus 8-encoded viral FLICE inhibitory protein protects against growth factor withdrawal-induced apoptosis via NF-κB activation. Blood 101, 1956–1961 (2003).

    Article  CAS  Google Scholar 

  27. Sun, Q., Matta, H. & Chaudhary, P. M. Kaposi's sarcoma associated herpes virus-encoded viral FLICE inhibitory protein activates transcription from HIV-1 Long Terminal Repeat via the classical NF-κB pathway and functionally cooperates with Tat. Retrovirology 2, 9 (2005).

    Article  Google Scholar 

  28. Djerbi, M. et al. The inhibitor of death receptor signalling, FLICE-inhibitory protein defines a new class of tumor progression factors. J. Exp. Med. 190, 1025–1032 (1999).

    Article  CAS  Google Scholar 

  29. Sun, Q., Zachariah, S. & Chaudhary, P. M. The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-κB activation. J. Biol. Chem. 278, 52437–52445 (2003).

    Article  CAS  Google Scholar 

  30. Grossmann, C., Podgrabinska, S., Skobe, M. & Ganem, D. Activation of NF-κB by the latent vFLIP gene of Kaposi's sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype. J. Virol. 80, 7179–7185 (2006).

    Article  CAS  Google Scholar 

  31. Chaudhary, P. M., Jasmin, A., Eby, M. T. & Hood, L. Modulation of the NF-κB pathway by virally encoded death effector domains-containing proteins. Oncogene 18, 5738–5746 (1999).

    Article  CAS  Google Scholar 

  32. Guasparri, I., Keller, S. A. & Cesarman, E. KSHV vFLIP is essential for the survival of infected lymphoma cells. J. Exp. Med. 199, 993–1003 (2004).

    Article  CAS  Google Scholar 

  33. Godfrey, A., Anderson, J., Papanastasiou, A., Takeuchi, Y. & Boshoff, C. Inhibiting primary effusion lymphoma by lentiviral vectors encoding short hairpin RNA. Blood 105, 2510–2518 (2005).

    Article  CAS  Google Scholar 

  34. Keller, S. A. et al. NF-κB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 107, 3295–3302 (2006).

    Article  CAS  Google Scholar 

  35. Ozturk, S., Schleich, K. & Lavrik, I. N. Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Exp. Cell Res. 318, 1324–1331 (2012).

    Article  CAS  Google Scholar 

  36. Matta, H. et al. Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-κB pathway independent of TRAF6, TAK1 and LUBAC. PLoS ONE 7, e36601 (2012).

    Article  CAS  Google Scholar 

  37. Liu, L. et al. The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the IκB kinase complex. J. Biol. Chem. 277, 13745–13751 (2002).

    Article  CAS  Google Scholar 

  38. Field, N. et al. KSHV vFLIP binds to IKK-γ to activate IKK. J. Cell Sci. 116, 3721–3728 (2003).

    Article  CAS  Google Scholar 

  39. Bagneris, C. et al. Crystal structure of a vFlip-IKKγ complex: insights into viral activation of the IKK signalosome. Mol. Cell 30, 620–631 (2008).

    Article  CAS  Google Scholar 

  40. Lee, S. H. et al. Novel phosphorylations of IKKγ/NEMO. mBio 3, e00411–12 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Matta, H. et al. A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-κB in a negative feedback manner. J. Biol. Chem. 286, 21555–21564 (2011).

    Article  CAS  Google Scholar 

  42. Honda, K., Takaoka, A. & Taniguchi, T. Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity 25, 349–360 (2006).

    Article  CAS  Google Scholar 

  43. Baresova, P., Pitha, P. M. & Lubyova, B. Distinct roles of Kaposi's sarcoma-associated herpesvirus-encoded viral interferon regulatory factors in inflammatory response and cancer. J. Virol. 87, 9398–9410 (2013).

    Article  CAS  Google Scholar 

  44. Lee, H. R. et al. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication. J. Virol. 88, 2183–2194 (2014).

    Article  Google Scholar 

  45. Seo, J. Y., Yaneva, R., Hinson, E. R. & Cresswell, P. Human cytomegalovirus directly induces the antiviral protein Viperin to enhance infectivity. Science 332, 1093–1097 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

C.L. is funded by the by American Cancer Society (grant RSG-11-121-01-CCG) and the US National Institutes of Health (NIH) (grants CA140964 and CA161436). B.-H.O is funded by the GRL Program (K20815000001) and KAIST Institute Cancer Metastasis Control Center (grant N1014002). J.U.J is funded by the NIH (grants CA082057, CA31363, CA115284, CA180779, AI073099, AI105809 and HL110609), the Global Research Laboratory (GRL) Program (K20815000001) from National Research Foundation of Korea, the Hastings Foundation and the Fletcher Jones Foundation.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Chengyu Liang or Jae U. Jung.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, C., Oh, BH. & Jung, J. Novel functions of viral anti-apoptotic factors. Nat Rev Microbiol 13, 7–12 (2015). https://doi.org/10.1038/nrmicro3369

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3369

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing