C-type Lectin Receptor Dectin-3 Mediates Trehalose 6,6′-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent NF-ĸB Activation [Signal Transduction]

September 8th, 2014 by Zhao, X.-Q., Zhu, L.-L., Chang, Q., Jiang, C., You, Y., Luo, T., Jia, X.-M., Lin, X.

Previous studies indicate that both Dectin-3 (also called MCL or Clec4d) and Mincle (also called Clec4e), two C-type lectin receptors (CLRs), can recognize Trehalose 6,6'-dimycolate (TDM), a cell wall component from mycobacteria, and induce potent innate immune responses. Interestingly, stimulation of Dectin-3 by TDM can also induce Mincle expression, which may enhance the host innate immune system to sense mycobacterium infection. However, the mechanism by which Dectin-3 induces Mincle expression is not fully defined. Here, we show that TDM-induced Mincle expression is dependent on Dectin-3-mediated NF-ĸB, but not NFAT, activation, and Dectin-3 induces NF-κB activation through the CARD9-BCL10-MALT1 complex. We found that bone marrow-derived macrophages (BMDMs) from Dectin-3-deficient mice were severely defective in the induction of Mincle expression in response to TDM stimulation. This defect is correlated with the failure of TDM-induced NF-ĸB activation in Dectin-3-deficient BMDMs. Consistently, inhibition of NF-κB, but not NFAT, impaired TDM-induced Mincle expression, while NF-ĸB, but not NFAT, binds to the Mincle promoter. Dectin-3-mediated NF-κB activation is dependent on the CARD9-Bcl10-MALT1 complex. Finally, mice deficiency in Dectin-3 or CARD9 produced much less pro-inflammatory cytokines and KLH-specific antibodies after immunization with an adjuvant containing TDM. Overall, this study provides the mechanism by which Dectin-3 induces Mincle expression in response to mycobacterium infection, which will have significant impact to improve adjuvant and design vaccine for anti-microbial infection.
  • Posted in Journal of Biological Chemistry, Publications
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