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Dok3–protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity
Jia Tong Loh, … , Yue Wang, Kong-Peng Lam
Jia Tong Loh, … , Yue Wang, Kong-Peng Lam
Published June 10, 2019
Citation Information: J Clin Invest. 2019;129(7):2717-2729. https://doi.org/10.1172/JCI126341.
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Research Article Immunology Infectious disease Article has an altmetric score of 3

Dok3–protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity

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Abstract

Invasive fungal infection is a serious health threat with high morbidity and mortality. Current antifungal drugs only demonstrate partial success in improving prognosis. Furthermore, mechanisms regulating host defense against fungal pathogens remain elusive. Here, we report that the downstream of kinase 3 (Dok3) adaptor negatively regulates antifungal immunity in neutrophils. Our data revealed that Dok3 deficiency increased phagocytosis, proinflammatory cytokine production, and netosis in neutrophils, thereby enhancing mutant mouse survival against systemic infection with a lethal dose of the pathogenic fungus Candida albicans. Biochemically, Dok3 recruited protein phosphatase 1 (PP1) to dephosphorylate Card9, an essential player in innate antifungal defense, to dampen downstream NF-κB and JNK activation and immune responses. Thus, Dok3 suppresses Card9 signaling, and disrupting Dok3-Card9 interaction or inhibiting PP1 activity represents therapeutic opportunities to develop drugs to combat candidaemia.

Authors

Jia Tong Loh, Shengli Xu, Jian Xin Huo, Susana Soo-Yeon Kim, Yue Wang, Kong-Peng Lam

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Figure 6

Inhibition of PP1 enhances Card9 phosphorylation and neutrophil antifungal responses.

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Inhibition of PP1 enhances Card9 phosphorylation and neutrophil antifung...
Purified Dok3+/+ neutrophils were untreated (UT) or pretreated with tautomycetin (TC) for 2.5 hours. (A and B) Cells were stimulated with zymosan (10 μg/ml) for 30 minutes. (A) Cell lysates were IP with a Card9-specific antibody, and precipitates were probed for p-Thr and Card9. Whole cell lysates were probed for Card9 and β-actin. Images are representative of 3 independent experiments. (B) Immunoblot analysis of cell lysates for p-IKKα/βS176/180, IKKα/β, p-JNKT183/Y185, and JNK. Images are representative of 3 independent experiments. (C) Analysis of TNF-α production by neutrophils pretreated with indicated concentrations of tautomycetin by flow cytometry. Graph indicates percentages of TNF-α+ neutrophils. Data are pooled from 2 independent experiments (n = 3–5). ***P = 0.0002, 1-way ANOVA.

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