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

Autor: Casas J; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain. javier.casas@uva.es.; Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003, Valladolid, Spain. javier.casas@uva.es., Meana C; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain., López-López JR; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, 47003, Valladolid, Spain., Balsinde J; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain., Balboa MA; Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain. mbalboa@ibgm.uva.es.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain. mbalboa@ibgm.uva.es.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Dec; Vol. 78 (24), pp. 8243-8260. Date of Electronic Publication: 2021 Nov 10.
DOI: 10.1007/s00018-021-03999-0
Abstrakt: 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 Ca 2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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