Pharmacological and genetic targeting of pPI4KA reveals its important role in maintaining plasma membrane PtdIns4p and PtdIns(4,5)p2 levels
OPEN The Journal of biological chemistry | 15 Jan 2014
N Bojjireddy, J Botyanszki, G Hammond, D Creech, R Peterson, DC Kemp, M Snead, R Brown, A Morrison, S Wilson, S Harrison, C Moore and T Balla
Phosphatidylinositol 4-kinase type IIIα (PI4KA) is a host factor essential for Hepatitis C virus (HCV) replication and hence is a target for drug development. PI4KA has also been linked to ER-exit sites and generation of plasma membrane phosphoinositides. Here we developed highly specific and potent inhibitors of PI4KA and conditional knockout mice to study the importance of this enzyme in vitro and in vivo. Our studies showed that PI4KA is essential for the maintenance of plasma membrane PtdIns(4,5)P2 pools but only during strong stimulation of receptors coupled to PLC activation. Pharmacological blockade of PI4KA in adult animals leads to sudden death closely correlating with the drugs ability to induce PtdIns(4,5)P2 depletion after agonist stimulation. Genetic inactivation of PI4KA also leads to death, however, the cause in this case is due to severe intestinal necrosis. These studies highlight the risks of targeting PI4KA as an anti HCV strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets.
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