title: 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.
abstract: 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.
authors.affiliation: From the Departments of Molecular and Cellular Oncology, and Immunology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Xue-Qiang
authors.initials: XQ
authors.lastname: Zhao
authors.affiliation: the Department of Immunology, School of Medicine, Tongji University, Shanghai 200092, China, and.
authors.forename: Le-Le
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: the Institute for Immunology, Tsinghua University, School of Medicine, Beijing 100084, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: From the Departments of Molecular and Cellular Oncology, and Immunology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Changying
authors.initials: C
authors.lastname: Jiang
authors.affiliation: From the Departments of Molecular and Cellular Oncology, and Immunology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.affiliation: the Institute for Immunology, Tsinghua University, School of Medicine, Beijing 100084, China.
authors.forename: Tianming
authors.initials: T
authors.lastname: Luo
authors.affiliation: the Department of Immunology, School of Medicine, Tongji University, Shanghai 200092, China, and jiaxm@tongji.edu.cn.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Jia
authors.affiliation: From the Departments of Molecular and Cellular Oncology, and Immunology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, xllin@mdanderson.org.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000378:metabolism*; D020169:Caspases / Q000172:deficiency / Q000378:metabolism*; D003311:Cord Factors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D055503:Protein Multimerization / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; C584161:Clec4d protein, mouse; C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D021122:Protein Subunits; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
keywords: Innate Immunity; Lectin; NF-kappa B (NF-κB); NF-κB Transcription Factor; Signal Transduction