title: Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency.
abstract: Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.
authors.affiliation: Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Henneman
authors.forename: M S
authors.initials: MS
authors.lastname: Schneiders
authors.forename: M
authors.initials: M
authors.lastname: Turkenburg
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
mesh_terms: D016022:Case-Control Studies; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D054078:Mevalonate Kinase Deficiency / Q000201:enzymology* / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D017368:Protein Prenylation; D021381:Protein Transport; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C107953:RAC1 protein, human; C066737:RHOA protein, human; D019821:Simvastatin; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
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