Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30374-9
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Funding
- German Research Council [GRK 1715, KO 4589/4-1]
- Phospholipid Research Center [AKO-2022-100/2-2, AKO-2019-070/2-1, AKO-2015-037/1-1]
- University of Jena [DRM/2013-05, 2.7-05]
- Strategy and Innovation Grant from the Free State of Thuringia [41-5507-2016]
- Leibniz ScienceCampus InfectoOptics [SAS-2015-HKI-LWC]
- Carl Zeiss foundation
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI)
- Federal Government of Germany
- State of Thuringia
- Interdisciplinary Center for Clinical Research of the University Hospital Jena [IZKF UKJ FF02]
- Federal Ministry of Education and Research [01EC1901B]
- MESI-STRAT project [754688]
- PoLiMeR Innovative Training Network (Marie Skodowska-Curie grant agreement) [812616]
- ARDRE COFUND Training Network (Marie Skodowska-Curie grant agreement) [847681]
- European Union
- German Tuberous Sclerosis Foundation
- Stichting TSC Fonds
- University of Innsbruck [316826]
- Tyrolian Research Fund [18903]
- Marie Curie Actions (MSCA) [812616, 847681] Funding Source: Marie Curie Actions (MSCA)
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The study reveals that PI(18:1/18:1) is a signaling lipid derived from SCD1 that connects fatty acid unsaturation with stress responses, regulating stress adaption, protecting against cell death, and promoting proliferation.
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.
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