| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 96 === Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, replicates primarily
at the endoplasmic reticulum and thereby triggers apoptosis of the infected cells. We
investigate hierarchical activation of the caspase network induced by JEV infection. We
found JEV activated initiator caspases-8 and -9 as well as effector caspase-3 in the
infected baby hamster kidney and mouse neuroblastoma (N18) cells. In neuronal N18
cells, JEV infection triggered cytochrome-c release from mitochondria, which in turn
activated caspases-9 and -3. Treatment of the JEV-infected N18 cells with cyclosporin A
or ruthenium red, which attenuates the mitochondrial injuries, could block activation of
caspases-9 or -3, typifying that in neuronal cells this apoptosis involves the mitochondrial
pathway. Alternatively, in caspase-3-deficient MCF-7 cells, JEV remained to readily
trigger a typical apoptotic response, including cytochrome-c release and a full activation
of caspases-9 and -8 along with caspase-6, indicating that JEV required no caspase-3 to
manifest caspase-8 activation and apoptosis. Interestingly, an FADD-dominant-negative
mutant, which interferes with transmission of the extracellular death signals through
Fas/TNF receptor into the cells, failed to block JEV-induced apoptosis and caspase-8
activation, implying that receptor oligomerization of the Fas/TNF pathway might not
participate in JEV-induced apoptosis. Together, our results illustrate that JEV infection
triggered caspase cascades involving initiator caspases-8 and -9, likely through FADD-independent but mitochondrion-dependent pathways.
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