期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 11, 页码 7038-7046出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806650200
关键词
-
资金
- Biomedical Research Council of A*STAR
Dectin-1 is a C-type lectin that recognizes beta-glucan in the cell walls of fungi and plays an important role in anti-fungal immunity. It signals via tyrosine kinase Syk and adaptor protein Card9 to activate NF-kappa B leading to proinflammatory cytokine production in dendritic cells (DCs). Other than this, not much else is known of the mechanism of Dectin-1 signaling. We demonstrate here that stimulation of DCs with zymosan triggers an intracellular Ca2+ flux that can be attenuated by a blocking anti-Dectin-1 antibody or by pre-treatment of cells with the phospholipase C( PLC) gamma-inhibitor U73122, suggesting that Dectin-1 signals via a PLC gamma pathway to induce Ca2+ flux in DCs. Interestingly, treatment of DCs with particulate curdlan, which specifically engages Dectin-1, results in the phosphorylation of both PLC gamma 1 and PLC gamma 2. However, we show that PLC gamma 2 is the critical enzyme for Dectin-1 signaling in DCs. PLC gamma 2-deficient DCs have drastic impairment of Ca2+ signaling and are defective in their secretion of interleukin 2 (IL-2), IL-6, IL-10, IL-12, IL-23, and tumor necrosis factor alpha. PLC gamma 2-deficient DCs also exhibit impaired activation of ERK and JNK MAPKs and AP-1 and NFAT transcription factors in response to Dectin-1 stimulation. In addition, PLC gamma 2-deficient DCs are also impaired in their activation of NF-kappa B upon Dectin-1 engagement due to defective assembly of the Card9-Bcl10-Malt1 complex and impaired IKK alpha/beta activation and I kappa B alpha degradation. Thus, our data indicate that pattern recognition receptors such as Dectin-1 could elicit Ca2+ signaling and that PLC gamma 2 is a critical player in the Dectin-1 signal transduction pathway.
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