Proteolytic activation of fatty acid synthase signals pan-stress resolution.

Autor: Wei H; Department of Pharmacology, UT Southwestern, Dallas, TX, USA., Weaver YM; Department of Pharmacology, UT Southwestern, Dallas, TX, USA., Yang C; Children's Medical Center Research Institute, UT Southwestern, Dallas, TX, USA., Zhang Y; Department of Pharmacology, UT Southwestern, Dallas, TX, USA., Hu G; Department of Internal Medicine, UT Southwestern, Dallas, TX, USA., Karner CM; Department of Internal Medicine, UT Southwestern, Dallas, TX, USA., Sieber M; Department of Physiology, UT Southwestern, Dallas, TX, USA., DeBerardinis RJ; Children's Medical Center Research Institute, UT Southwestern, Dallas, TX, USA.; Howard Hughes Medical Institute, UT Southwestern, Dallas, TX, USA., Weaver BP; Department of Pharmacology, UT Southwestern, Dallas, TX, USA. benjamin.weaver@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Jan; Vol. 6 (1), pp. 113-126. Date of Electronic Publication: 2024 Jan 02.
DOI: 10.1038/s42255-023-00939-z
Abstrakt: Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis elegans. FASN is well established for biosynthesis of the fatty acid palmitate. Our results demonstrate FASN promoting an anti-inflammatory profile apart from palmitate synthesis. Redox-dependent proteolysis of limited amounts of FASN by caspase activates a C-terminal fragment sufficient to downregulate multiple aspects of stress responsiveness, including gene expression, metabolic programs and lipid droplets. The FASN C-terminal fragment signals stress resolution in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted male mouse liver. As downregulation of stress responses is critical to health, our findings provide a potential pathway to control diverse aspects of stress responses.
(© 2024. The Author(s).)
Databáze: MEDLINE
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