title: 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.
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.
authors.affiliation: From the Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Naveen
authors.initials: N
authors.lastname: Bojjireddy
authors.forename: Janos
authors.initials: J
authors.lastname: Botyanszki
authors.forename: Gerald
authors.initials: G
authors.lastname: Hammond
authors.forename: Donald
authors.initials: D
authors.lastname: Creech
authors.forename: Richard
authors.initials: R
authors.lastname: Peterson
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Kemp
authors.forename: Mark
authors.initials: M
authors.lastname: Snead
authors.forename: Randy
authors.initials: R
authors.lastname: Brown
authors.forename: Alastair
authors.initials: A
authors.lastname: Morrison
authors.forename: Steve
authors.initials: S
authors.lastname: Wilson
authors.forename: Steve
authors.initials: S
authors.lastname: Harrison
authors.forename: Chris
authors.initials: C
authors.lastname: Moore
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D018390:Gene Targeting; D057809:HEK293 Cells; D006526:Hepatitis C / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D010738:Type C Phospholipases
keywords: Angiotensin II; G Protein-coupled Receptors; Phosphatidylinositol; Phosphatidylinositol Kinase; Phospholipase C