期刊
NATURE CELL BIOLOGY
卷 21, 期 3, 页码 338-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0270-5
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资金
- AIRC [IG-15307, IG-21392]
- WCR [15-1192]
- CARIPARO Eccellenza 2017
- University of Padua BIRD grants
- AIRC Hard ROCK Cafe Fellowship
- UPMC 'Interface pour le Vivant' doctoral programme
- AIRC Special Program Molecular Clinical Oncology '5 per mille' [10016]
Extracellular matrix (ECM) mechanical cues have powerful effects on cell proliferation, differentiation and death. Here, starting from an unbiased metabolomics approach, we identify synthesis of neutral lipids as a general response to mechanical signals delivered by cell-matrix adhesions. Extracellular physical cues reverberate on the mechanical properties of the Golgi apparatus and regulate the Lipin-1 phosphatidate phosphatase. Conditions of reduced actomyosin contractility lead to inhibition of Lipin-1, accumulation of SCAP/SREBP to the Golgi apparatus and activation of SREBP transcription factors, in turn driving lipid synthesis and accumulation. This occurs independently of YAP/TAZ, mTOR and AMPK, and in parallel to feedback control by sterols. Regulation of SREBP can be observed in a stiffened diseased tissue, and contributes to the pro-survival activity of ROCK inhibitors in pluripotent stem cells. We thus identify a general mechanism centered on Lipin-1 and SREBP that links the physical cell microenvironment to a key metabolic pathway.
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