Thürmer, MariaGollowitzer, AndréPein, HelmutNeukirch, KonstantinGelmez, ElifWaltl, LorenzWielsch, NatalieWinkler, RenéLöser, KonstantinGrander, JuliaHotze, MadlenHarder, SönkeDöding, AnnikaMeßner, MartinaTroisi, FabianaArdelt, MaximilianSchlüter, HartmutPachmayr, JohannaGutiérrez-Gutiérrez, ÓscarRudolph, Karl LenhardThedieck, KathrinSchulze-Späte, UlrikeGonzález Estévez, CristinaKosan, ChristianSvatoš, AlešKwiatkowski, MarcelKoeberle, Andreas2024-11-222024-11-222022-05-272041-1723https://hdl.handle.net/2445/216695Cytotoxic 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-phos- pho-(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.21 p.application/pdfengcc-by (c) Thürmer M et al., 2022http://creativecommons.org/licenses/by/4.0/Proteïnes quinasesEstrès (Fisiologia)AutofàgiaProtein kinasesStress (Physiology)Autophagyinfo:eu-repo/semantics/article7512822024-11-22info:eu-repo/semantics/openAccess