C-type Lectin Receptor Dectin-3 Mediates Trehalose 6,6′-Dimycolate (TDM)-induced Mincle Expression through CARD9/Bcl10/MALT1-dependent Nuclear Factor (NF)-κB Activation

• Published in: The Journal of biological chemistry Vol. 289; no. 43; pp. 30052 - 30062
• Main Authors: Zhao, Xue-Qiang, Zhu, Le-Le, Chang, Qing, Jiang, Changying, You, Yun, Luo, Tianming, Jia, Xin-Ming, Lin, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.10.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - metabolism; Adjuvants, Immunologic - pharmacology; Animals; B-Cell CLL-Lymphoma 10 Protein; CARD Signaling Adaptor Proteins - deficiency; CARD Signaling Adaptor Proteins - metabolism; Caspases - deficiency; Caspases - metabolism; Cord Factors - pharmacology; Cytokines - biosynthesis; Gene Expression Regulation - drug effects; Humans; Immunology; Lectins, C-Type - deficiency; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Models, Biological; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Neoplasm Proteins - deficiency; Neoplasm Proteins - metabolism; NF-kappa B - metabolism; NFATC Transcription Factors - metabolism; Promoter Regions, Genetic - genetics; Protein Multimerization - drug effects; Protein Subunits - metabolism; Receptors, Immunologic - deficiency; Receptors, Immunologic - metabolism; Signal Transduction - drug effects; Transcription Factor RelA - metabolism; Lectin; Signal Transduction; Innate Immunity; NF-κB Transcription Factor; NF-kappa B (NF-κB)
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.588574

Previous studies indicate that both Dectin-3 (also called MCL or Clec4d) and Mincle (also called Clec4e), two C-type lectin receptors, 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-κB, but not nuclear factor of activated T-cells (NFAT), activation, and Dectin-3 induces NF-κB activation through the CARD9-BCL10-MALT1 complex. We found that bone marrow-derived macrophages 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-κB activation in Dectin-3-deficient bone marrow-derived macrophages. Consistently, inhibition of NF-κB, but not NFAT, impaired TDM-induced Mincle expression, whereas NF-κB, but not NFAT, binds to the Mincle promoter. Dectin-3-mediated NF-κB activation is dependent on the CARD9-Bcl10-MALT1 complex. Finally, mice deficient for Dectin-3 or CARD9 produced much less proinflammatory cytokines and keyhole limpet hemocyanin (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 antimicrobial infection.