RT info:eu-repo/semantics/article
T1 Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling
A1 Casas, Javier
A1 Meana, Clara
A1 López-López, José Ramón
A1 Balsinde, Jesús
A1 Balboa, María A.
AB Exposure 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.
SN 1420-682X
YR 2021
FD 2021
LK https://uvadoc.uva.es/handle/10324/65532
UL https://uvadoc.uva.es/handle/10324/65532
LA eng
NO 1.Casas, J., Meana, C., López-López, J. R., Balsinde, J. & Balboa, M. A. Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling. Cell Mol Life Sci 1–18 (2021) doi:10.1007/s00018-021-03999-0.
NO Producción Científica
DS UVaDOC
RD 18-sep-2024