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  2. Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels

Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels

  • J Biol Chem. 2014 Feb 28;289(9):6120-32. doi: 10.1074/jbc.M113.531426.
Naveen Bojjireddy 1 Janos Botyanszki Gerald Hammond Donald Creech Richard Peterson Daniel C Kemp Mark Snead Randy Brown Alastair Morrison Steve Wilson Steve Harrison Chris Moore Tamas Balla
Affiliations

Affiliation

  • 1 From the Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and.
Abstract

Phosphatidylinositol 4-kinase type IIIα (PI4KA) is a host factor essential for hepatitis C virus replication and hence is a target for drug development. PI4KA has also been linked to endoplasmic reticulum exit sites and generation of plasma membrane phosphoinositides. Here, we developed highly specific and potent inhibitors of PI4KA and conditional knock-out 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 phosphatidylinositol 4,5-bisphosphate pools but only during strong stimulation of receptors coupled to Phospholipase C activation. Pharmacological blockade of PI4KA in adult Animals leads to sudden death closely correlating with the drug's ability to induce phosphatidylinositol 4,5-bisphosphate 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-hepatitis C virus strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets.

Keywords

Angiotensin II; G Protein-coupled Receptors; Phosphatidylinositol; Phosphatidylinositol Kinase; Phospholipase C.

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