NEUROPROTECTIVE MODULATION OF PRO-APOPTOTIC POTASSIUM CURRENTS BY THE HEPATITIS C VIRUS NON-STRUCTURAL PROTEIN 5A

We and others have shown that potassium loss is a requisite apoptotic event in mammalian cortical and midbrain neuronal systems. Potassium loss after oxidative injury is mediated through an increase in the soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated channel insertion of the delayed rectifier voltage-gated potassium channel Kv2.1. This occurs through the dual phosphorylation mechanism of S800 and Y124, mediated by p38 and Src respectively. Inhibiting the potassium current surge is enough to block neuronal cell death in models of neuronal injury. Thus, targeting this cellular apoptotic pathway could provide novel therapeutic strategies in neuroprotection for diseases such as Alzheimer’s, Parkinson’s, and ischemic stroke. Recently the hepatitis C virus (HCV) non-structural 5A (NS5A) protein was found to confer anti-apoptotic properties through the same pathway in hepatocytes, contributing to viral persistence. Here we show that expression of NS5A (genotype 1b) in neurons limits Kv2.1 functional expression, modulates the pro-apoptotic potassium current surge, and is neuroprotective. Importantly, we define a mechanism for this regulation whereby NS5A1b inhibits Src phosphorylation at the Y124 residue of Kv2.1. These anti-apoptotic effects are not as profound in cells expressing NS5A of the 1a genotype, suggesting that these effects are genotype-selective. Preliminary results inhibiting Casein Kinase II, known to phosphorylate NS5A, lead us to speculate that post-translational modifications are required for K+ current modulation. Our results indicate that NS5A1b maintains neuronal viability after injury via Kv2.1 current modulation, and that this could translate to improved therapies in neuroprotection. It is therefore likely that this pathway is critical for NS5A-induced adaptation of host cell activity for maximizing and perpetuating hepatic viral infection