3.2.2 Regulation of WNV proteins on apoptosis
Yang et al.(Joo-Sung et al., 2002)
demonstrated for the first time that transfection of WNV-C in neuronal
and non-neuronal cells can cause inflammation and apoptosis. Further
studies have shown that WNV-C induces apoptosis by destroying
mitochondrial membranes and activating caspase-9 and caspase-3, and the
3’-terminal region of the capsid protein is related to its
apoptosis-inducing function. In addition, the WNV-C protein
phosphorylated by protein kinase C
(PKC) can enhance its binding and nucleus co-localization with HDM2
protein, a p53 negative regulator, thereby stabilizing p53 and then
inducing its apoptosis target protein
Bax(Bhuvanakantham, Cheong, & Ng, 2010;
M. Yang et al., 2010). Despite the
substantial evidence supporting the pro-apoptotic effect of capsid
protein, Urbanowski et al.(Urbanowski &
Hobman, 2013) found that WNV-C inhibits cell apoptosis by activating
Phosphatidylinositol-3-kinase
(PI3K)-Akt pro-survival pathway in four mammalian cells (A549, HEK293T,
Vero-76, BHK-21). The discrepancy between these reports may be due to
the capsid protein containing an 18-amino-acid-residue signal peptide of
prM in the earlier reports.
In 2006, Liu et al.(W. J. Liu et al.,
2006) mutated the alanine at position 30 of the WNV-NS2A protein to
proline (A30P) and found that the virulence of the virusviral was
significantly weakened. Further, Melian et al.
(Melian et al., 2013) used this mutant
and wild strain to infect IFN⁃β-deficient cells, and found that the DNA
degradation of the mutant group was reduced and the number of
TUNEL-labeled positive cells decreased significantly, indicating that
the WNV⁃NS2A protein plays a role in IFN-independent apoptosis.
Moreover, the expression of NS2B-NS3 or NS3 protein, but not NS2B, can
induce apoptosis. Further studies have showed that WNV-NS3 can trigger
apoptosis mediated either individually or together by the caspases-8 and
-3 pathways, and the protease and helicase domains of NS3 protein are
both essential for inducing
apoptosis(Ramanathan et al., 2006). The
thorough knowledge of the apoptotic pathways driven by NS2B-NS3 and NS3
will undoubtedly provide valuable insights for development of novel
therapeutics for this viral infection.