West Nile virus capsid protein induces p53-mediated apoptosis via the sequestration of HDM2 to the nucleolus.
The capsid protein of the West Nile virus (WNV) functions as an apoptotic agonist via the induction of mitochondrial dysfunction and the activation of caspases-9 and -3. Here, we have determined that the WNV capsid (WNVCp) is capable of binding to and sequestering HDM2 into the nucleolus. WNVCp was shown to interfere with the formation of the HDM2 and p53 complex, thereby causing the stabilization of p53 and the subsequent induction of its target apoptotic protein, Bax. Whereas WNVCp was capable of inducing the p53-dependent apoptotic process in wild-type mouse embryonic fibroblasts (MEF) or SH-SY5Y cells, it exerted no significant effects on p53-null MEF or on p53-knockdown SH-SY5Y cells. This suggests that WNVCp-mediated apoptosis requires p53. Furthermore, when WNV was transfected into cells, endogenous Hdm2 and WNVCp were able to interact physically. WNVCp expressed in wild-type MEF proved able to induce the translocation of the endogenous Hdm2 into the nucleolus. Consistently, WNV was highly pathogenic in the presence of p53, and was less so in the absence of p53. The results of these studies suggest that the apoptotic mechanism mediated by WNV might occur in accordance in a fashion similar to that of the tumour-suppressing mechanism mediated by ARF.
Yang
Mi-Ran
MR
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 440-746, Korea.
Lee
Sung Ryul
SR
Oh
Wonkyung
W
Lee
Eun-Woo
EW
Yeh
Jung-Yong
JY
Nah
Jin-Ju
JJ
Joo
Yi-Seok
YS
Shin
Jaekyoon
J
Lee
Han-Woong
HW
Pyo
Suhkneung
S
Song
Jaewhan
J
D000818:Animals; D017209:Apoptosis; D036022:Capsid Proteins / Q000378:metabolism*; D002460:Cell Line; D002466:Cell Nucleolus / Q000737:chemistry*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014902:West Nile virus / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D036022:Capsid Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
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