1887

Journal of General Virology

Volume 91, Issue 6

The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1 Free

Abstract

It has previously been reported that influenza A virus infection activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition, it has been shown that the mutant influenza A virus PR8-SH3-mf-1, which is unable to activate the PI3K/Akt pathway, is more pro-apoptotic than the wild-type (WT) virus. However, the molecular pathways involved in regulating this process remain unknown. Here, it is reported that, although both WT and PR8-SH3-mf-1 viruses induced apoptosis, the PR8-SH3-mf-1 virus consistently showed greater potential to induce mitochondrial membrane disruption, cytochrome release, and translocation and conformational change of Bax than the WT virus. Furthermore, the PR8-SH3-mf-1 virus was unable to phosphorylate apoptosis signal-regulating kinase 1 (ASK1) but induced higher levels of c-jun N-terminal kinase (JNK) phosphorylation than the WT virus. Blocking JNK activity could inhibit virus-induced Bax activation and apoptosis. These results reveal that, during influenza A virus infection, the PI3K/Akt pathway negatively regulates the JNK pathway via ASK1, thereby inhibiting JNK-dependent, Bax-mediated apoptosis.

  • Received:
  • Accepted:
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2010-06-01
2019-11-17
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References

  1. Aikin, R., Maysinger, D. & Rosenberg, L. ( 2004; ). Cross-talk between phosphatidylinositol 3-kinase/AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets. Endocrinology 145, 4522–4531.[CrossRef]
    [Google Scholar]
  2. Autret, A., Martin-Latil, S., Mousson, L., Wirotius, A., Petit, F., Arnoult, D., Colbere-Garapin, F., Estaquier, J. & Blondel, B. ( 2007; ). Poliovirus induces Bax-dependent cell death mediated by c-Jun NH2-terminal kinase. J Virol 81, 7504–7516.[CrossRef]
    [Google Scholar]
  3. Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E., Frisch, S. & Reed, J. C. ( 1998; ). Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318–1321.[CrossRef]
    [Google Scholar]
  4. Clarke, P., Meintzer, S. M., Wang, Y., Moffitt, L. A., Richardson-Burns, S. M., Johnson, G. L. & Tyler, K. L. ( 2004; ). JNK regulates the release of proapoptotic mitochondrial factors in reovirus-infected cells. J Virol 78, 13132–13138.[CrossRef]
    [Google Scholar]
  5. Cory, S. & Adams, J. M. ( 2002; ). The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2, 647–656.[CrossRef]
    [Google Scholar]
  6. Danial, N. N. & Korsmeyer, S. J. ( 2004; ). Cell death: critical control points. Cell 116, 205–219.[CrossRef]
    [Google Scholar]
  7. Ehrhardt, C., Wolff, T., Pleschka, S., Planz, O., Beermann, W., Bode, J. G., Schmolke, M. & Ludwig, S. ( 2007; ). Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J Virol 81, 3058–3067.[CrossRef]
    [Google Scholar]
  8. García-Sastre, A., Egorov, A., Matassov, D., Brandt, S., Levy, D. E., Durbin, J. E., Palese, P. & Muster, T. ( 1998; ). Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330.[CrossRef]
    [Google Scholar]
  9. Hale, B. G., Jackson, D., Chen, Y. H., Lamb, R. A. & Randall, R. E. ( 2006; ). Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling. Proc Natl Acad Sci U S A 103, 14194–14199.[CrossRef]
    [Google Scholar]
  10. Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., Takagi, M., Matsumoto, K., Miyazono, K. & Gotoh, Y. ( 1997; ). Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90–94.[CrossRef]
    [Google Scholar]
  11. Jackson, D., Killip, M. J., Galloway, C. S., Russell, R. J. & Randall, R. E. ( 2010; ). Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K). Virology 396, 94–105.[CrossRef]
    [Google Scholar]
  12. Kim, A. H., Khursigara, G., Sun, X., Franke, T. F. & Chao, M. V. ( 2001; ). Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21, 893–901.[CrossRef]
    [Google Scholar]
  13. Kim, H. E., Du, F., Fang, M. & Wang, X. ( 2005; ). Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci U S A 102, 17545–17550.[CrossRef]
    [Google Scholar]
  14. Kim, B. J., Ryu, S. W. & Song, B. J. ( 2006; ). JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281, 21256–21265.[CrossRef]
    [Google Scholar]
  15. Lalier, L., Cartron, P. F., Juin, P., Nedelkina, S., Manon, S., Bechinger, B. & Vallette, F. M. ( 2007; ). Bax activation and mitochondrial insertion during apoptosis. Apoptosis 12, 887–896.[CrossRef]
    [Google Scholar]
  16. Lam, W. Y., Tang, J. W., Yeung, A. C., Chiu, L. C., Sung, J. J. & Chan, P. K. ( 2008; ). Avian influenza virus A/HK/483/97(H5N1) NS1 protein induces apoptosis in human airway epithelial cells. J Virol 82, 2741–2751.[CrossRef]
    [Google Scholar]
  17. Lei, K., Nimnual, A., Zong, W. X., Kennedy, N. J., Flavell, R. A., Thompson, C. B., Bar-Sagi, D. & Davis, R. J. ( 2002; ). The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH2-terminal kinase. Mol Cell Biol 22, 4929–4942.[CrossRef]
    [Google Scholar]
  18. Li, Y., Anderson, D. H., Liu, Q. & Zhou, Y. ( 2008; ). Mechanism of influenza A virus NS1 protein interaction with the p85β, but not the p85α, subunit of phosphatidylinositol 3-kinase (PI3K) and up-regulation of PI3K activity. J Biol Chem 283, 23397–23409.[CrossRef]
    [Google Scholar]
  19. Lin, C., Zimmer, S. G., Lu, Z., Holland, R. E., Jr, Dong, Q. & Chambers, T. M. ( 2001; ). The involvement of a stress-activated pathway in equine influenza virus-mediated apoptosis. Virology 287, 202–213.[CrossRef]
    [Google Scholar]
  20. Ludwig, S., Wang, X., Ehrhardt, C., Zheng, H., Donelan, N., Planz, O., Pleschka, S., García-Sastre, A., Heins, G. & Wolff, T. ( 2002; ). The influenza A virus NS1 protein inhibits activation of Jun N-terminal kinase and AP-1 transcription factors. J Virol 76, 11166–11171.[CrossRef]
    [Google Scholar]
  21. Mao, H., Tu, W., Qin, G., Law, H. K., Sia, S. F., Chan, P. L., Liu, Y., Lam, K. T., Zheng, J. & other authors ( 2009; ). Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol 83, 9215–9222.[CrossRef]
    [Google Scholar]
  22. Martin-Latil, S., Mousson, L., Autret, A., Colbere-Garapin, F. & Blondel, B. ( 2007; ). Bax is activated during rotavirus-induced apoptosis through the mitochondrial pathway. J Virol 81, 4457–4464.[CrossRef]
    [Google Scholar]
  23. Maruoka, S., Hashimoto, S., Gon, Y., Nishitoh, H., Takeshita, I., Asai, Y., Mizumura, K., Shimizu, K., Ichijo, H. & Horie, T. ( 2003; ). ASK1 regulates influenza virus infection-induced apoptotic cell death. Biochem Biophys Res Commun 307, 870–876.[CrossRef]
    [Google Scholar]
  24. McLean, J. E., Datan, E., Matassov, D. & Zakeri, Z. F. ( 2009; ). Lack of Bax prevents influenza A virus-induced apoptosis and causes diminished viral replication. J Virol 83, 8233–8246.[CrossRef]
    [Google Scholar]
  25. Mori, I., Komatsu, T., Takeuchi, K., Nakakuki, K., Sudo, M. & Kimura, Y. ( 1995; ). In vivo induction of apoptosis by influenza virus. J Gen Virol 76, 2869–2873.[CrossRef]
    [Google Scholar]
  26. Nencioni, L., De, C. G., Sgarbanti, R., Amatore, D., Aquilano, K., Marcocci, M. E., Serafino, A., Torcia, M., Cozzolino, F. & other authors ( 2009; ). Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: impact on virally induced apoptosis and viral replication. J Biol Chem 284, 16004–16015.[CrossRef]
    [Google Scholar]
  27. Olsen, C. W., Kehren, J. C., Dybdahl-Sissoko, N. R. & Hinshaw, V. S. ( 1996; ). bcl-2 alters influenza virus yield, spread, and hemagglutinin glycosylation. J Virol 70, 663–666.
     [Google Scholar]
  28. Park, M. S., Shaw, M. L., Muñoz-Jordan, J., Cros, J. F., Nakaya, T., Bouvier, N., Palese, P., García-Sastre, A. & Basler, C. F. ( 2003; ). Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDV V protein and the Nipah virus V, W, and C proteins. J Virol 77, 1501–1511.[CrossRef]
    [Google Scholar]
  29. Razvi, E. S. & Welsh, R. M. ( 1995; ). Apoptosis in viral infections. Adv Virus Res 45, 1–60.
     [Google Scholar]
  30. Schultz-Cherry, S. & Hinshaw, V. S. ( 1996; ). Influenza virus neuraminidase activates latent transforming growth factor beta. J Virol 70, 8624–8629.
     [Google Scholar]
  31. Schultz-Cherry, S., Dybdahl-Sissoko, N., Neumann, G., Kawaoka, Y. & Hinshaw, V. S. ( 2001; ). Influenza virus NS1 protein induces apoptosis in cultured cells. J Virol 75, 7875–7881.[CrossRef]
    [Google Scholar]
  32. Shin, Y. K., Li, Y., Liu, Q., Anderson, D. H., Babiuk, L. A. & Zhou, Y. ( 2007a; ). SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signaling pathway activation. J Virol 81, 12730–12739.[CrossRef]
    [Google Scholar]
  33. Shin, Y. K., Liu, Q., Tikoo, S. K., Babiuk, L. A. & Zhou, Y. ( 2007b; ). Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J Gen Virol 88, 942–950.[CrossRef]
    [Google Scholar]
  34. Shin, Y. K., Liu, Q., Tikoo, S. K., Babiuk, L. A. & Zhou, Y. ( 2007c; ). Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 88, 13–18.[CrossRef]
    [Google Scholar]
  35. Takizawa, T., Matsukawa, S., Higuchi, Y., Nakamura, S., Nakanishi, Y. & Fukuda, R. ( 1993; ). Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells. J Gen Virol 74, 2347–2355.[CrossRef]
    [Google Scholar]
  36. Tournier, C., Hess, P., Yang, D. D., Xu, J., Turner, T. K., Nimnual, A., Bar-Sagi, D., Jones, S. N., Flavell, R. A. & Davis, R. J. ( 2000; ). Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870–874.[CrossRef]
    [Google Scholar]
  37. Tsuruta, F., Sunayama, J., Mori, Y., Hattori, S., Shimizu, S., Tsujimoto, Y., Yoshioka, K., Masuyama, N. & Gotoh, Y. ( 2004; ). JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 23, 1889–1899.[CrossRef]
    [Google Scholar]
  38. Wang, X. S., Diener, K., Jannuzzi, D., Trollinger, D., Tan, T. H., Lichenstein, H., Zukowski, M. & Yao, Z. ( 1996; ). Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem 271, 31607–31611.[CrossRef]
    [Google Scholar]
  39. Zamarin, D., García-Sastre, A., Xiao, X., Wang, R. & Palese, P. ( 2005; ). Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 1, e4 [CrossRef]
    [Google Scholar]
  40. Zhirnov, O. P., Konakova, T. E., Wolff, T. & Klenk, H. D. ( 2002; ). NS1 protein of influenza A virus down-regulates apoptosis. J Virol 76, 1617–1625.[CrossRef]
    [Google Scholar]
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The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1
J. Gen. Virol. 91, 1439 (2010); https://doi.org/10.1099/vir.0.018465-0
/content/journal/jgv/10.1099/vir.0.018465-0
/content/journal/jgv/10.1099/vir.0.018465-0
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