Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling

Jianhui Ma; Qian Sun; Ruifang Mi; Hongbing Zhang

doi:10.1016/j.jgg.2011.10.002

Volume 38 Issue 11

Nov. 2011

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Article Navigation > Journal of Genetics and Genomics > 2011 > 38(11): 533-537

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Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling

doi: 10.1016/j.jgg.2011.10.002

Department of Physiology and Pathophysiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China

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Corresponding author: E-mail address: hbzhang2006@gmail.com (Hongbing Zhang)
Received Date: 2011-10-06
Accepted Date: 2011-10-13
Rev Recd Date: 2011-10-12

Available Online: 2011-10-23

Publish Date: 2011-11-20

Abstract

Abstract

Of the few avian influenza viruses that have crossed the species barrier to infect humans, the highly pathogenic influenza A (H5N1) strain has claimed the lives of more than half of the infected patients. With largely unknown mechanism of lung injury by H5N1 infection, acute respiratory distress syndrome (ARDS) is the major cause of death among the victims. Here we present the fact that H5N1 caused autophagic cell death through suppression of mTOR signaling. Inhibition of autophagy, either by depletion of autophagy gene Beclin1 or by autophagy inhibitor 3-methyladenine (3-MA), significantly reduced H5N1 mediated cell death. We suggest that autophagic cell death may contribute to the development of ARDS in H5N1 influenza patients and inhibition of autophagy could therefore become a novel strategy for the treatment of H5N1 infection.
- Avian influenza,
- H5N1,
- Autophagy,
- mTOR,
- TSC2,
- PTEN

Present address: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

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References(27)

References

[1]	Alva, A.S., Gultekin, S.H., Baehrecke, E.H. Autophagy in human tumors: cell survival or death? Cell Death Differ., 11 (2004),pp. 1046-1048
[2]	Amaral, J.D., Xavier, J.M., Steer, C.J. et al. The role of p53 in apoptosis Discov. Med., 9 (2010),pp. 145-152
[3]	Cao, Y., Klionsky, D.J. Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein Cell Res., 17 (2007),pp. 839-849
[4]	Chan, M.C., Chan, R.W., Yu, W.C. et al. Influenza H5N1 virus infection of polarized human alveolar epithelial cells and lung microvascular endothelial cells Respir. Res., 10 (2009),p. 102
[5]	Chotpitayasunondh, T., Ungchusak, K., Hanshaoworakul, W. et al. Human disease from influenza A (H5N1), Thailand, 2004 Emerg. Infect. Dis., 11 (2005),pp. 201-209
[6]	Daidoji, T., Koma, T., Du, A. et al. H5N1 avian influenza virus induces apoptotic cell death in mammalian airway epithelial cells J. Virol., 82 (2008),pp. 11294-11307
[7]	de Jong, M.D., Hien, T.T. Avian influenza A (H5N1) J. Clin. Virol., 35 (2006),pp. 2-13
[8]	Diaz-Troya, S., Perez-Perez, M.E., Florencio, F.J. et al. The role of TOR in autophagy regulation from yeast to plants and mammals Autophagy, 4 (2008),pp. 851-865
[9]	Fiebig, L., Soyka, J., Buda, S. et al. Avian influenza A(H5N1) in humans: new insights from a line list of World Health Organization confirmed cases, September 2006 to August 2010 Euro. Surveill., 16 (2011),pp. 1-10
[10]	Inoki, K., Zhu, T., Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival Cell, 115 (2003),pp. 577-590
[11]	Kwiatkowski, D.J., Zhang, H., Bandura, J.L. et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells Hum. Mol. Genet., 11 (2002),pp. 525-534
[12]	Levine, B. Cell biology: autophagy and cancer Nature, 446 (2007),pp. 745-747
[13]	Levine, B., Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest., 115 (2005),pp. 2679-2688
[14]	Li, C., , Eisfeld, A.J., Hatta, Y. et al. Host regulatory network response to infection with highly pathogenic H5N1 avian influenza virus J. Virol., 85 (2011),pp. 10955-10967
[15]	Li, Y., Inoki, K., Vacratsis, P. et al. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3 J. Biol. Chem., 278 (2003),pp. 13663-13671
[16]	Ma, J., Meng, Y., Kwiatkowski, D.J. et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade J. Clin. Invest., 120 (2010),pp. 103-114
[17]	Manning, B.D., Tee, A.R., Logsdon, M.N. et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway Mol. Cell, 10 (2002),pp. 151-162
[18]	Mi, R., Ma, J., Zhang, D. et al. Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model J. Genet. Genomics, 36 (2009),pp. 355-361
[19]	Pallepati, P., Averill-Bates, D. Mild thermotolerance induced at 40 degrees C increases antioxidants and protects HeLa cells against mitochondrial apoptosis induced by hydrogen peroxide: role of p53 Arch. Biochem. Biophys., 495 (2010),pp. 97-111
[20]	Parkhitko, A., Myachina, F., Morrison, T.A. et al. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent Proc. Natl. Acad. Sci. USA, 108 (2011),pp. 12455-12460
[21]	Potter, C.J., Pedraza, L.G., Xu, T. Akt regulates growth by directly phosphorylating Tsc2 Nat. Cell Biol., 4 (2002),pp. 658-665
[22]	Thanh, T.T., van Doorn, H.R., de Jong, M.D. Human H5N1 influenza: current insight into pathogenesis Int. J. Biochem. Cell Biol., 40 (2008),pp. 2671-2674
[23]	Turpin, E., Luke, K., Jones, J. et al. Influenza virus infection increases p53 activity: role of p53 in cell death and viral replication J. Virol., 79 (2005),pp. 8802-8811
[24]	Zhang, H., Bajraszewski, N., Wu, E. et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR J. Clin. Invest., 117 (2007),pp. 730-738
[25]	Zhang, H., Cicchetti, G., Onda, H. et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR J. Clin. Invest., 112 (2003),pp. 1223-1233
[26]	Zhou, Z., Jiang, X., Liu, D. et al. Autophagy is involved in influenza A virus replication Autophagy, 5 (2009),pp. 321-328
[27]	Zhu, H., Wu, H., Liu, X. et al. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells Autophagy, 5 (2009),pp. 816-823