PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling
Maria Thürmer, André Gollowitzer, Helmut Pein, Konstantin Neukirch, Elif Gelmez, Lorenz Waltl, Natalie Wielsch, René Winkler, Konstantin Löser, Julia Grander, Madlen Hotze, Sönke Harder, Annika Döding, Martina Meßner, Fabiana Troisi, Maximilian A. Ardelt, Hartmut Schlüter, Johanna Pachmayr, Óscar Gutiérrez‐Gutiérrez, K. Lenhard Rudolph, Kathrin Thedieck, Ulrike Schulze‐Späte, Cristina González‐Estévez, Christian Kosan, Aleš Svatoš, Marcel Kwiatkowski, Andreas Koeberle
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.