title: Role of p38 mitogen-activated protein kinase in linking stearoyl-CoA desaturase-1 activity with endoplasmic reticulum homeostasis.
abstract: Endoplasmic reticulum (ER) homeostasis is regulated by a network of signaling pathways to which stearoyl-CoA desaturase (SCD)-1, p38 mitogen-activated protein kinase (MAPK) and the unfolded protein response (UPR) belong. Because all these pathways are located at the interface of cell cycle control and cell stress, we hypothesized a cross-regulation. Interference with SCD-1, either by small interfering (si)RNA or the specific SCD-1 inhibitor CAY10566 (EC₅₀ 1 µM; ≥ 24 h), specifically induced phosphorylation and thus activation of p38 MAPK in NIH-3T3 mouse fibroblasts (1.5- to 2-fold; 48 hours). During lipotoxic and cell cycle stress, prolonged activation of p38 MAPK due to SCD-1 inhibition induced ER stress, the UPR, and ER/Golgi remodeling as shown by Western blot and immunofluorescence microscopy (1.2- to 3.5-fold). Specific inhibition of p38 MAPK by Skepinone-L [half maximal inhibitory concentration (IC₅₀) 25-50 nM] reversed these effects (at 1 µM; 48 hours). The specificity by which SCD-1 modulates the phospholipid composition and inhibits p38 MAPK signaling (among survival/stress pathways), thereby preventing ER stress (but not other SCD-1-dependent responses), suggests selective protein-lipid interactions. Palmitoleoyl/oleoyl-phosphatidylinositol (PI) was accordingly identified as potential lipid mediator using chromatography-coupled ESI tandem mass spectrometry. We conclude that the negative regulation of p38 MAPK mediates the protective effects of SCD-1 on ER homeostasis under distinct stress conditions.
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany andreas.koeberle@uni-jena.de.
authors: Andreas
authors: A
authors: Koeberle
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Carlo
authors: C
authors: Pergola
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Hideo
authors: H
authors: Shindou
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Solveigh C
authors: SC
authors: Koeberle
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Takao
authors: T
authors: Shimizu
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Stefan A
authors: SA
authors: Laufer
authors: *Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Leibniz Institute of Age Research, Fritz-Lipmann-Institute, Jena, Germany; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany.
authors: Oliver
authors: O
authors: Werz
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D056148:Chromatography, Reverse-Phase; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D010168:Palmitates / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D003986:Dibenzocycloheptenes; D004791:Enzyme Inhibitors; D010168:Palmitates; D010743:Phospholipids; C572387:skepinone-L; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: bioactive lipid; fatty acid; lipidomics; phospholipid; unfolded protein response