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 Ardelt, Hartmut Schlüter, Johanna Pachmayr, Óscar Gutiérrez-Gutiérrez, Karl Lenhard Rudolph, Kathrin Thedieck, Ulrike Schulze-Späte, Cristina González-Estévez, Christian Kosan, Aleš Svatoš, Marcel Kwiatkowski and Andreas Koeberle ()
Additional contact information
Maria Thürmer: Friedrich-Schiller-University Jena
André Gollowitzer: University of Innsbruck
Helmut Pein: Friedrich-Schiller-University Jena
Konstantin Neukirch: University of Innsbruck
Elif Gelmez: Friedrich-Schiller-University Jena
Lorenz Waltl: University of Innsbruck
Natalie Wielsch: Max Planck Institute for Chemical Ecology
René Winkler: Friedrich-Schiller-University Jena
Konstantin Löser: Friedrich-Schiller-University Jena
Julia Grander: University of Innsbruck
Madlen Hotze: University of Innsbruck
Sönke Harder: University Medical Center Hamburg-Eppendorf
Annika Döding: University Hospital Jena, Friedrich-Schiller-University Jena
Martina Meßner: Pharmaceutical Biology, LMU Munich
Fabiana Troisi: Friedrich-Schiller-University Jena
Maximilian Ardelt: Pharmaceutical Biology, LMU Munich
Hartmut Schlüter: University Medical Center Hamburg-Eppendorf
Johanna Pachmayr: Pharmaceutical Biology, LMU Munich
Óscar Gutiérrez-Gutiérrez: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Karl Lenhard Rudolph: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Kathrin Thedieck: University of Innsbruck
Ulrike Schulze-Späte: University Hospital Jena, Friedrich-Schiller-University Jena
Cristina González-Estévez: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Christian Kosan: Friedrich-Schiller-University Jena
Aleš Svatoš: Max Planck Institute for Chemical Ecology
Marcel Kwiatkowski: University of Innsbruck
Andreas Koeberle: Friedrich-Schiller-University Jena

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30374-9

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