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bioRxiv · 10.1101/2020.12.22.424011

GPCR-mediated Activation of PLCg2 Initiates Dysregulated Recruitment of Neutrophils in Cold-induced Urticaria in PLAID Patients

xu, x.·wen, x.·bhimani, s.·moosa, a.·parsons, d.·jin, t.
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Abstract

The current dogma is that chemoattractants G protein coupled receptors (GPCRs) activate {beta} phospholipase C (PLC{beta}) while receptor tyrosine kinases (RTKs) activate {gamma} phospholipase C (PLC{gamma}). Here, we show that chemoattractant/GPCR-mediated membrane recruitment of PLC{gamma}2 constitutes GPCR-mediated phospholipase C (PLC) signaling and is essential for neutrophil polarization and migration during GPCR-mediated chemotaxis. In response to a chemoattractant stimulation, cells lacking PLC{gamma}2 (plcg2kd) displayed altered dynamics of diacylglycerol (DAG) production and calcium response; increased Ras/PI3K/Akt activation; elevated GSK3 phosphorylation and cofilin activation; impaired dynamics of actin polymerization; and consequently defects in cell polarization and migration during chemotaxis. At low temperature, neutrophils expressing the gain-of-function mutant of PLC{gamma}2 ({Delta}686) displayed better chemotaxis than the cells expressing wild-type PLC{gamma}2. The study provides a molecular mechanism for the dysregulated recruitment and activation of neutrophils in cold-induced urticaria in PLC{gamma}2-associated antibody deficiency and immune dysregulation (PLAID) patients bearing gain-of-function mutations of PLC{gamma}2.

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xu, x., wen, x., bhimani, s., moosa, a., parsons, d., jin, t.. 2020-12-22. GPCR-mediated Activation of PLCg2 Initiates Dysregulated Recruitment of Neutrophils in Cold-induced Urticaria in PLAID Patients. https://doi.org/10.1101/2020.12.22.424011

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