FIGURE 8.

A model of NS5A interference with MLK3/p38/Kv2.1 signaling. HCV infection and RNA replication triggers the elevated production of reactive oxygen species (ROS), which activates MLK3, leading to activation of p38MAPK. In turn p38MAPK phosphorylates serine 800 of Kv2.1, which is a key phosphorylation event involved in the insertion of Kv2.1 into the plasma membrane. The upsurge in the efflux of K⁺ lowers the intracellular concentration of K⁺, causing an alteration of ionic homeostasis. At the same time MLK3 stimulates the induction of apoptosis. In this study, we show that NS5A inhibits MLK3 activation, thereby blocking both the phosphorylation and activation of Kv2.1, and MLK3-mediated apoptosis.