title: A phosphatidic acid binding/nuclear localization motif determines lipin1 function in lipid metabolism and adipogenesis.
abstract: Lipins are phosphatidic acid phosphatases with a pivotal role in regulation of triglyceride and glycerophospholipid metabolism. Lipin1 is also an amplifier of PGC-1α, a nuclear coactivator of PPAR-α responsive gene transcription. Lipins do not contain recognized membrane-association domains, but interaction of these enzymes with cellular membranes is necessary for access to their phospholipid substrate. We identified a role for a conserved polybasic amino acid motif in an N-terminal domain previously implicated as a determinant of nuclear localization in selective binding of lipin1β to phosphatidic acid, using blot overlay assays and model bilayer membranes. Studies using lipin1β polybasic motif variants establish that this region is also critical for nuclear import and raise the possibility that nuclear/cytoplasmic shuttling of lipin1β is regulated by PA. We used pharmacological agents and lipin1β polybasic motif mutants to explore the role of PA-mediated membrane association and nuclear localization on lipin1β function in phospholipid metabolism and adipogenic differentiation. We identify a role for the lipin1 polybasic motif as both a lipid binding motif and a primary nuclear localization sequence. These two functions are necessary for full expression of the biological activity of the protein in intracellular lipid metabolism and transcriptional control of adipogenesis.
authors.affiliation: Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY 40536-0200, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ren
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Federico
authors.forename: Huiyan
authors.initials: H
authors.lastname: Huang
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Tracy
authors.initials: T
authors.lastname: Drennan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: D008081:Liposomes; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010712:Phosphatidic Acids; D011993:Recombinant Fusion Proteins; D028901:alpha Karyopherins; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D010739:Phospholipase D