The involvement of survival signaling pathways in rubella-virus induced apoptosis

Cooray, Samantha; Jin, Li; Best, Jennifer M

Inhibition of the MEK1/2 in RK13 cells by U0126 resulted in necrotic monolayer destruction and a significant decrease in cell viability. XTT assay and light microscopy demonstrated that RV infection appeared to delay the effect of U0126. As discussed above, RV infection stimulates ERK activity, downstream of MEK, and may therefore counteract the effect of the inhibitor. Despite this, U0126 impaired RV replication, growth, and induction of apoptosis. Therefore it appears that although RV infection slows the cell cycle progression, cells must be cycling and metabolizing normally for RV replication to occur. ERK1/2 phosphorylation has also been observed during infection with a number of other viruses, and inhibition of ERK1/2 signaling by U0126 has consistently been shown to be detrimental to virus growth. Infection of Jurkat cells with CVB3, for example, leads to up-regulation of ERK1/2 phosphorylation, and elevated levels of phosphorylated ERK1/2 have been observed in the myocardium of mice susceptible to CVB3-induced myocarditis [38] . Treatment of cultured cells with U0126 reduced CVB3 titers and inhibited the release of virus progeny [38, 39] . Similarly, HCMV infection in human embryonic lung fibroblasts (HELs) has been shown to stimulate biphasic activation of MEK1/2 and ERK1/2, and treatment of infected cells with U0126 reduced viral DNA replication, protein production and virus titer [40] . Influenza A virus infection in vitro has also been shown to stimulate biphasic activation of MEK1/2 and ERK1/2, and U0126 treatment prevented export of ribonucleoprotein complexes from the nucleus and inhibited virus production [24] . Inhibition of MEK1/2 during HIV infection has been demonstrated to reduce infectivity, but unlike the other viruses mentioned herein, did not affect protein levels or virus production [25] . These findings, along with the results of this study, suggest that signaling downstream of MEK1/2 and ERK1/2 is important for viral infectivity and efficient virus replication and growth in vitro.