Infection with influenza A virus causes acute respiratory tract infections in humans and may lead to lethal diseases including pneumonia. Identifying host factors that are involved in the severity of infectious diseases caused by influenza A virus is considered important for the prevention and treatment of these viral infections. This report demonstrated that Siva-1 is crucial for the induction of apoptosis caused by infection with influenza A virus and is involved in virus replication. Susceptibility to apoptosis induced by influenza A virus infection was increased in human lung-derived A549 cells, which stably express Siva-1. In addition, induction of apoptosis after influenza A virus infection was strongly inhibited by knockdown of Siva-1 expression. Furthermore, the replication of influenza A virus was significantly suppressed in A549 cells in which Siva-1 expression was inhibited and the effect of Siva-1 knockdown was eliminated by treatment with Z-VAD-FMK. These findings suggest that the caspase-dependent pathway for induction of apoptosis is involved in Siva-1-mediated influenza A virus replication.


Article metrics loading...

Loading full text...

Full text loading...



  1. Abou-Sleiman, P. M., Muqit, M. M. & Wood, N. W.(2006). Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7, 207–219.[CrossRef] [Google Scholar]
  2. Ashkenazi, A. & Dixit, V. M.(1998). Death receptors: signaling and modulation. Science 281, 1305–1308.[CrossRef] [Google Scholar]
  3. Barkinge, J. L., Gudi, R., Sarah, H., Chu, F., Borthakur, A., Prabhakar, B. S. & Prasad, K. V.(2009). The p53-induced Siva-1 plays a significant role in cisplatin-mediated apoptosis. J Carcinog 8, 2.[CrossRef] [Google Scholar]
  4. Brown, J. M. & Attardi, L. D.(2005). The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5, 231–237. [Google Scholar]
  5. Cao, C., Ren, X., Kharbanda, S., Koleske, A., Prasad, K. V. & Kufe, D.(2001). The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress. J Biol Chem 276, 11465–11468.[CrossRef] [Google Scholar]
  6. Cheung, C. Y., Poon, L. L., Lau, A. S., Luk, W., Lau, Y. L., Shortridge, K. F., Gordon, S., Guan, Y. & Peiris, J. S.(2002). Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831–1837.[CrossRef] [Google Scholar]
  7. Chu, F., Borthakur, A., Sun, X., Barkinge, J., Gudi, R., Hawkins, S. & Prasad, K. V.(2004). The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis. Apoptosis 9, 83–95.[CrossRef] [Google Scholar]
  8. Chu, F., Barkinge, J., Hawkins, S., Gudi, R., Salgia, R. & Kanteti, P. V.(2005). Expression of Siva-1 protein or its putative amphipathic helical region enhances cisplatin-induced apoptosis in breast cancer cells: effect of elevated levels of BCL-2. Cancer Res 65, 5301–5309.[CrossRef] [Google Scholar]
  9. Dubrez-Daloz, L., Dupoux, A. & Cartier, J.(2008). IAPs: more than just inhibitors of apoptosis proteins. Cell Cycle 7, 1036–1046.[CrossRef] [Google Scholar]
  10. Engelhardt, O. G. & Fodor, E.(2006). Functional association between viral and cellular transcription during influenza virus infection. Rev Med Virol 16, 329–345.[CrossRef] [Google Scholar]
  11. Ehrhardt, C., Marjuki, H., Wolff, T., Nürnberg, B., Planz, O., Pleschka, S. & Ludwig, S.(2006). Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 8, 1336–1348.[CrossRef] [Google Scholar]
  12. Gudi, R., Barkinge, J., Hawkins, S., Chu, F., Manicassamy, S., Sun, Z., Duke-Cohan, J. S. & Prasad, K. V.(2006). Siva-1 negatively regulates NF-κB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD). Oncogene 25, 3458–3462.[CrossRef] [Google Scholar]
  13. Hajra, K. M. & Liu, J. R.(2004). Apoptosome dysfunction in human cancer. Apoptosis 9, 691–704.[CrossRef] [Google Scholar]
  14. Hale, B. G. & Randall, R. E.(2007). PI3K signalling during influenza A virus infections. Biochem Soc Trans 35, 186–187.[CrossRef] [Google Scholar]
  15. Hatta, M., Asano, Y., Masunaga, K., Ito, T., Okazaki, K., Toyoda, T., Kawaoka, Y., Ishihama, A. & Kida, H.(2000). Mapping of functional domains on the influenza A virus RNA polymerase PB2 molecule using monoclonal antibodies. Arch Virol 145, 1947–1961.[CrossRef] [Google Scholar]
  16. Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y.(2001). Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842.[CrossRef] [Google Scholar]
  17. Hennet, T., Peterhans, E. & Stocker, R.(1992). Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus. J Gen Virol 73, 39–46.[CrossRef] [Google Scholar]
  18. Hinshaw, V. S., Olsen, C. W., Dybdahl-Sissoko, N. & Evans, D.(1994). Apoptosis: a mechanism of cell killing by influenza A and B viruses. J Virol 68, 3667–3673. [Google Scholar]
  19. Ikeda, Y., Shinozuka, J., Miyazawa, T., Kurosawa, K., Izumiya, Y., Nishimura, Y., Nakamura, K., Cai, J., Fujita, K. & other authors(1998). Apoptosis in feline panleukopenia virus-infected lymphocytes. J Virol 72, 6932–6936. [Google Scholar]
  20. Ishikawa, E., Nakazawa, M., Yoshinari, M. & Minami, M.(2005). Role of tumor necrosis factor-related apoptosis-inducing ligand in immune response to influenza virus infection in mice. J Virol 79, 7658–7663.[CrossRef] [Google Scholar]
  21. Iwai, A., Hasumura, Y., Nojima, T. & Takegami, T.(2003). Hepatitis C virus nonstructural protein NS3 binds to Sm-D1, a small nuclear ribonucleoprotein associated with autoimmune disease. Microbiol Immunol 47, 601–611.[CrossRef] [Google Scholar]
  22. Johnson, N. P. & Mueller, J.(2002). Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bull Hist Med 76, 105–115.[CrossRef] [Google Scholar]
  23. Kobasa, D., Takada, A., Shinya, K., Hatta, M., Halfmann, P., Theriault, S., Suzuki, H., Nishimura, H., Mitamura, K. & other authors(2004). Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 431, 703–707.[CrossRef] [Google Scholar]
  24. Lin, F. T., Lai, Y. J., Makarova, N., Tigyi, G. & Lin, W. C.(2007). The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival. J Biol Chem 282, 37759–37769.[CrossRef] [Google Scholar]
  25. Ludwig, S. & Planz, O.(2008). Influenza viruses and the NF-κB signaling pathway – towards a novel concept of antiviral therapy. Biol Chem 389, 1307–1312. [Google Scholar]
  26. Majno, G. & Joris, I.(1995). Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146, 3–15. [Google Scholar]
  27. Makhija, R. & Kingsnorth, A. N.(2002). Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg 9, 401–410.[CrossRef] [Google Scholar]
  28. Martin, T. R. & Wurfel, M. M.(2008). A TRIFfic perspective on acute lung injury. Cell 133, 208–210.[CrossRef] [Google Scholar]
  29. Mok, C. K., Lee, D. C., Cheung, C. Y., Peiris, M. & Lau, A. S.(2007). Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. J Gen Virol 88, 1275–1280.[CrossRef] [Google Scholar]
  30. Nakamura, T. & Lipton, S. A.(2009). Cell death: protein misfolding and neurodegenerative diseases. Apoptosis 14, 455–468.[CrossRef] [Google Scholar]
  31. Nakamura, R., Maeda, N., Shibata, K., Yamada, H., Kase, T. & Yoshikai, Y.(2010). Interleukin-15 is critical in the pathogenesis of influenza A virus-induced acute lung injury. J Virol 84, 5574–5582.[CrossRef] [Google Scholar]
  32. Neumann, G. & Kawaoka, Y.(2006). Host range restriction and pathogenicity in the context of influenza pandemic. Emerg Infect Dis 12, 881–886.[CrossRef] [Google Scholar]
  33. Opferman, J. T. & Korsmeyer, S. J.(2003). Apoptosis in the development and maintenance of the immune system. Nat Immunol 4, 410–415.[CrossRef] [Google Scholar]
  34. Prasad, K. V., Ao, Z., Yoon, Y., Wu, M. X., Rizk, M., Jacquot, S. & Schlossman, S. F.(1997). CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci U S A 94, 6346–6351.[CrossRef] [Google Scholar]
  35. Py, B., Slomianny, C., Auberger, P., Petit, P. X. & Benichou, S.(2004). Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway. J Immunol 172, 4008–4017.[CrossRef] [Google Scholar]
  36. Resch, U., Schichl, Y. M., Winsauer, G., Gudi, R., Prasad, K. & de Martin, R.(2009). Siva1 is a XIAP-interacting protein that balances NFκB and JNK signalling to promote apoptosis. J Cell Sci 122, 2651–2661.[CrossRef] [Google Scholar]
  37. Samejima, K. & Earnshaw, W. C.(2005). Trashing the genome: the role of nucleases during apoptosis. Nat Rev Mol Cell Biol 6, 677–688.[CrossRef] [Google Scholar]
  38. Shin, Y. K., Liu, Q., Tikoo, S. K., Babiuk, L. A. & Zhou, Y.(2007). Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J Gen Virol 88, 942–950.[CrossRef] [Google Scholar]
  39. Shinya, K., Hamm, S., Hatta, M., Ito, H., Ito, T. & Kawaoka, Y.(2004). PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320, 258–266.[CrossRef] [Google Scholar]
  40. Shuyu, E., Lai, Y.-J., Tsukahara, R., Chen, C.-S., Fujiwara, Y., Yue, J., Yu, J.-H., Guo, H., Kihara, A. & other authors(2009). Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect. J Biol Chem 284, 14558–14571.[CrossRef] [Google Scholar]
  41. Subbarao, E. K., London, W. & Murphy, B. R.(1993). A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67, 1761–1764. [Google Scholar]
  42. Suzuki, Y.(2005). Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses. Biol Pharm Bull 28, 399–408.[CrossRef] [Google Scholar]
  43. Suzuki, D., Yamada, A., Amano, T., Yasuhara, R., Kimura, A., Sakahara, M., Tsumaki, N., Takeda, S., Tamura, M. & other authors(2009). Essential mesenchymal role of small GTPase Rac1 in interdigital programmed cell death during limb development. Dev Biol 335, 396–406.[CrossRef] [Google Scholar]
  44. 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]
  45. Tanaka, M. & Miyake, Y.(2007). Apoptotic cell clearance and autoimmune disorder. Curr Med Chem 14, 2892–2897.[CrossRef] [Google Scholar]
  46. Trilla, A., Trilla, G. & Daer, C.(2008). The 1918 “Spanish flu” in Spain. Clin Infect Dis 47, 668–673.[CrossRef] [Google Scholar]
  47. Tsuda, Y., Isoda, N., Sakoda, Y. & Kida, H.(2009). Factors responsible for plaque formation of A/duck/Siberia/272/1998 (H13N6) influenza virus on MDCK cells. Virus Res 140, 194–198.[CrossRef] [Google Scholar]
  48. Tumpey, T. M., Lu, X., Morken, T., Zaki, S. R. & Katz, J. M.(2000). Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans. J Virol 74, 6105–6116.[CrossRef] [Google Scholar]
  49. Wang, Y., Wu, T. R., Cai, S., Welte, T. & Chin, Y. E.(2000). Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-κB activation. Mol Cell Biol 20, 4505–4512.[CrossRef] [Google Scholar]
  50. Wurzer, W. J., Planz, O., Ehrhardt, C., Giner, M., Silberzahn, T., Pleschka, S. & Ludwig, S.(2003). Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 22, 2717–2728.[CrossRef] [Google Scholar]
  51. Wurzer, W. J., Ehrhardt, C., Pleschka, S., Berberich-Siebelt, F., Wolff, T., Walczak, H., Planz, O. & Ludwig, S.(2004). NF-κB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem 279, 30931–30937.[CrossRef] [Google Scholar]
  52. Xue, L., Chu, F., Sun, X., Borthakur, A., Ramarao, M., Pandey, P., Wu, M., Schlossman, S. F. & Prasad, K. V.(2002). Siva-1 binds to and inhibits BCL-XL-mediated protection against UV radiation-induced apoptosis. Proc Natl Acad Sci U S A 99, 6925–6930.[CrossRef] [Google Scholar]
  53. Yoon, Y., Ao, Z., Cheng, Y., Schlossman, S. F. & Prasad, K. V.(1999). Murine Siva-1 and Siva-2, alternate splice forms of the mouse Siva gene, both bind to CD27 but differentially transduce apoptosis. Oncogene 18, 7174–7179.[CrossRef] [Google Scholar]
  54. Zhou, J., Law, H. K., Cheung, C. Y., Ng, I. H., Peiris, J. S. & Lau, Y. L.(2006). Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages. J Infect Dis 193, 945–953.[CrossRef] [Google Scholar]
  55. Zhu, X. D. & Sadowski, P. D.(1995). Cleavage-dependent ligation by the FLP recombinase. Characterization of a mutant FLP protein with an alteration in a catalytic amino acid. J Biol Chem 270, 23044–23054.[CrossRef] [Google Scholar]

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error