Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling

Cell Mol Life Sci. 2021 Nov 10. doi: 10.1007/s00018-021-03999-0. Online ahead of print.ABSTRACTExposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca2+ elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca2+ responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation.PMID:34757442 | DOI:10.1007/s00018-021-03999-0

Source: Cellular and Molecular Life Sciences : CMLS - November 10, 2021 Category: Cytology Authors: Javier Casas Clara Meana Jos é Ramón López-López Jes ús Balsinde Mar ía A Balboa Source Type: research