PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

Thuermer, Maria; Gollowitzer, Andre; Pein, Helmut; Neukirch, Konstantin; Gelmez, Elif; Waltl, Lorenz; Wielsch, Natalie; Winkler, Rene; Loeser, Konstantin; Grander, Julia; Hotze, Madlen; Harder, Sonke; Doeding, Annika; Messner, Martina; Troisi, Fabiana; Ardelt, Maximilian; Schlueter, Hartmut; Pachmayr, Johanna; Gutierrez-Gutierrez, Oscar; Rudolph, Karl Lenhard; Thedieck, Kathrin; Schulze-Spaete, Ulrike; Gonzalez-Estevez, Cristina; Kosan, Christian; Svatos, Ales; Kwiatkowski, Marcel und Koeberle, Andreas (2022): PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling. In: Nature Communications, Bd. 13, Nr. 1, 2982

Abstract

Cytotoxic stress activates stress-activated kinases, initiates adaptive mechanisms, including the unfolded protein response (UPR) and autophagy, and induces programmed cell death. Fatty acid unsaturation, controlled by stearoyl-CoA desaturase (SCD)1, prevents cytotoxic stress but the mechanisms are diffuse. Here, we show that 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] is a SCD1-derived signaling lipid, which inhibits p38 mitogen-activated protein kinase activation, counteracts UPR, endoplasmic reticulum-associated protein degradation, and apoptosis, regulates autophagy, and maintains cell morphology and proliferation. SCD1 expression and the cellular PI(18:1/18:1) proportion decrease during the onset of cell death, thereby repressing protein phosphatase 2 A and enhancing stress signaling. This counter-regulation applies to mechanistically diverse death-inducing conditions and is found in multiple human and mouse cell lines and tissues of Scd1-defective mice. PI(18:1/18:1) ratios reflect stress tolerance in tumorigenesis, chemoresistance, infection, high-fat diet, and immune aging. Together, PI(18:1/18:1) is a lipokine that links fatty acid unsaturation with stress responses, and its depletion evokes stress signaling. Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• Sprache: Englisch