STAT3 Regulation of Citrate Synthase Is Essential during the Initiation of Lymphocyte Cell Growth

Citrate is a required carbon precursor for de novo fatty acid and membrane lipid synthesis. However, the pathways regulating intracellular citrate, particularly during the initial transition from a resting state to cell growth, remain unclear. Here, we show that STAT3 is among the first signaling events activated in resting lymphocytes following growth factor stimulation. During this period, the inhibition of STAT3 blocks the expression of citrate synthase (CS) and reduces the levels of intracellular citrate. As a consequence of CS loss and the reduction in citrate, cells are unable to grow or proliferate in response to extracellular growth factors. These effects were due to STAT3-dependent transcriptional regulation of CS, as exogenous addition of citrate could restore fatty acid synthesis, cell growth, and proliferation. Taken together, our studies reveal that transcription-dependent control of CS is essential for regulating the initiation of cell growth.