Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection

被引:172
作者
Lee, CJ
Liao, CL
Lin, YL
机构
[1] Acad Sinica, Inst Biomed Sci, Natl Def Med Ctr, Taipei 11529, Taiwan
[2] Acad Sinica, Grad Inst Life Sci, Dept Microbiol & Immunol, Taipei 11529, Taiwan
[3] Acad Sinica, Genom Res Ctr, Taipei 11529, Taiwan
关键词
D O I
10.1128/JVI.79.13.8388-8399.2005
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Flaviviruses such as dengue virus (DEN) and Japanese encephalitis virus (JEV) are medically important in humans. The lipid kinase, phosphatidylinositol 3-kinase (PI3K) and its downstream target Akt have been implicated in the regulation of diverse cellular functions such as proliferation, and apoptosis. Since JEV and DEN appear to trigger apoptosis in cultured cells at a rather late stage of infection, we evaluated the possible roles of the PI31K/Akt signaling pathway in flavivirus-infected cells. We found that Akt phosphorylation was noticeable in the JEV- and DEN serotype 2 (DEN-2)-infected neuronal N18 cells in an early, transient, PI3K- and lipid raft-dependent manner. Blocking of PI3K activation by its specific inhibitor LY294002 or wortmannin greatly enhanced virus-induced cytopathic effects (CPEs), even at an early stage of infection, but had no effect on virus production. This severe CPE was characterized as apoptotic cell death as evidenced by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining and cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Mechanically, the initiator and effector caspases involved are mainly caspase-9 and caspase-6, since only a pan-caspase inhibitor and the inhibitors preferentially target caspase-9 and -6, but not the ones antagonizing caspase-8, -3, or -7 alleviated the levels of PARP cleavage after virus infection and PI3K blockage. Furthermore, Bcl-2 appears to be a crucial mediator downstream of PI3K/Akt signaling, since overexpression of Bcl-2 reduced virus-induced apoptosis even when PI3K activation was repressed. Collectively, our results suggest an antiapoptotic role for the PI3K/Akt pathway triggered by JEV and DEN-2 to protect infected cells from early apoptotic cell death.
引用
收藏
页码:8388 / 8399
页数:12
相关论文
共 79 条
  • [1] NEUROTRANSMITTER SYNTHESIS BY NEUROBLASTOMA CLONES
    AMANO, T
    NIRENBERG, M
    RICHELSON, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1972, 69 (01) : 258 - +
  • [2] [Anonymous], FIELDS VIROLOGY
  • [3] Structures of immature flavivirus particles
    Zhang, Y
    Corver, J
    Chipman, PR
    Zhang, W
    Pletnev, SV
    Sedlak, D
    Baker, TS
    Strauss, JH
    Kuhn, RJ
    Rossmann, MG
    [J]. EMBO JOURNAL, 2003, 22 (11) : 2604 - 2613
  • [4] WORTMANNIN IS A POTENT PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR - THE ROLE OF PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE IN NEUTROPHIL RESPONSES
    ARCARO, A
    WYMANN, MP
    [J]. BIOCHEMICAL JOURNAL, 1993, 296 : 297 - 301
  • [5] The activation of p38 and apoptosis by the inhibition of ERK is antagonized by the phosphoinositide S-kinase/Akt pathway
    Berra, E
    Diaz-Meco, MT
    Moscat, J
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (17) : 10792 - 10797
  • [6] Lost in translation: Dysregulation of cap-dependent translation and cancer
    Bjornsti, MA
    Houghton, PJ
    [J]. CANCER CELL, 2004, 5 (06) : 519 - 523
  • [7] Translation elongation factor-1 alpha interacts with the 3' stem-loop region of West Nile virus genomic RNA
    Blackwell, JL
    Brinton, MA
    [J]. JOURNAL OF VIROLOGY, 1997, 71 (09) : 6433 - 6444
  • [8] Advances in protein kinase B signalling:: AKTion on multiple fronts
    Brazil, DP
    Yang, ZZ
    Hemmings, BA
    [J]. TRENDS IN BIOCHEMICAL SCIENCES, 2004, 29 (05) : 233 - 242
  • [9] Functions of lipid rafts in biological membranes
    Brown, DA
    London, E
    [J]. ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 : 111 - 136
  • [10] The phosphoinositide 3-kinase pathway
    Cantley, LC
    [J]. SCIENCE, 2002, 296 (5573) : 1655 - 1657