CARD9 controls a non-TLR signaling pathway for innate anti-fungal immunity

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Nature (Impact Factor: 41.46). 09/2006; 442(7103):651-6. DOI: 10.1038/nature04926
Source: PubMed


Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module.

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Available from: Tim D Sparwasser
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    • "Our results from Trim62 À/À mice suggest that TRIM62-mediated regulation of CARD9 activation is critical in the context of fungal infection. These data complement previous studies reporting critical roles for CARD9 and PKCd during C. albicans infection and suggest that TRIM62 is a novel member of this pathway and is important for anti-fungal immunity (Gross et al., 2006; Strasser et al., 2012). Furthermore, we found that Trim62 À/À mice, similar to Card9 À/À mice, are more susceptible to DSS colitis, underscoring the importance of this pathway in intestinal homeostasis and fortifying previous reports on the relationship between fungi and IBD (Chehoud et al., 2015; Richard et al., 2015; Romani, 2011). "
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    ABSTRACT: CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.
    Full-text · Article · Oct 2015 · Immunity
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    • "CARD9 is an important part of the pathway engaged by the pattern recognition receptor Dectin-1, which is responsible for initiating many innate immune responses to fungal elements, including, ultimately, the development of Th17 cells as discussed previously.17 Consistent with its essential role as a “danger signal” capable of recognizing Candida-derived fungal elements AR mutations in Dectin-1 and CARD9 have also been associated with the CMC phenotype. "
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    • "Previous studies suggest that -glucans from C. albicans activate Dectin-1–mediated NF-B activation through a CARD9- dependent pathway (Gross et al., 2006). To further investigate the role of CARD9 in Dectin-1–induced signaling pathways in response to fungal infection, BM-derived macrophages (BMDMs) or BM-derived DCs (BMDCs) from WT (Card9 +/+ ) or CARD9-deficient (Card9 / ) mice were stimulated with WT or mnn5 strain of C. albicans yeast. "
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    ABSTRACT: Dectin-1 functions as a pattern recognition receptor for sensing fungal infection. It has been well-established that Dectin-1 induces innate immune responses through caspase recruitment domain-containing protein 9 (CARD9)-mediated NF-κB activation. In this study, we find that CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands, such as curdlan or Candida albicans yeast. In contrast, we find that CARD9 regulates H-Ras activation by linking Ras-GRF1 to H-Ras, which mediates Dectin-1-induced extracellular signal-regulated protein kinase (ERK) activation and proinflammatory responses when stimulated by their ligands. Mechanistically, Dectin-1 engagement initiates spleen tyrosine kinase (Syk)-dependent Ras-GRF1 phosphorylation, and the phosphorylated Ras-GRF1 recruits and activates H-Ras through forming a complex with CARD9, which leads to activation of ERK downstream. Finally, we show that inhibiting ERK activation significantly accelerates the death of C. albicans-infected mice, and this inhibitory effect is dependent on CARD9. Together, our studies reveal a molecular mechanism by which Dectin-1 induces H-Ras activation that leads to ERK activation for host innate immune responses against fungal infection.
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