| Popis: |
Mechanical cues coming from the extracellular matrix (ECM) are key factors in the control of tissue homeostasis in physiology and disease. Cells can sense these physical cues and measure external resisting forces by adjusting their actomyosin cytoskeleton, which in turn regulates intracellular signalling pathways to orchestrate a proper cell response. Thus, ECM stiffness is important for many biological aspects such as proliferation, differentiation and migration. Very little is known instead, about its impact on cellular metabolism, and the molecular players involved in this process are largely unknown. Starting from an unbiased metabolomics approach, we found lipid accumulation as a general response to mechanical signals and to low tension conditions. Mechanicistically, this accumulation is associated with a decreased Lipin1 phosphatidate phosphatase localization at ER/Golgi membranes and decreased Lipin1 activity which ultimately lead to nuclear translocation and activation of SREBP1/2 transcription factors. This occurs independently of YAP/TAZ and mTOR, and in parallel to the feedback control by sterols. Led by our findings, we discovered a coherent regulation of SREBP in stiffened pathological human tissues, and identified SREBP as required for the pro-survival activity of ROCK inhibitors in embryonic stem cells. We thus propose that SREBP is a general mechanism that links the physical cell microenvironment to a key metabolic pathway |
