Dectin-1, a C-type lectin, plays important roles in the induction of antifungal immunity. Caspase recruitment domain-containing protein 9 (CARD9) is essential for the dectin-1-induced production of cytokines through the activation of NF-κB. However, the molecular mechanisms underlying the dectin-1-mediated activation of CARD9 have not been fully elucidated. Recently, we reported that the adaptor protein SH3 domain-binding protein 2 (3BP2) is required for the dectin-1-induced production of cytokines and activation of NF-κB, although the relationship between 3BP2 and CARD9 in dectin-1-mediated signaling remains unclear. Here, we report that 3BP2 is required for dectin-1-induced expression of several genes that may contribute to antifungal immunity in bone marrow-derived dendritic cells (BMDCs). The results of reporter assays using HEK-293T cells indicate that 3BP2 induces CARD9-mediated activation of NF-κB through B-cell leukemia/lymphoma 10, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and TNF receptor-associated factor 6-dependent mechanisms. In addition, we show that 3BP2 induces CARD9-mediated ubiquitination of cellular proteins and that MALT1 cleaves 3BP2 in a CARD9-dependent manner. Furthermore, we show that 3BP2 is required for the ubiquitination, in addition to the activation, of MALT1, which leads to MALT1-depenedent cleavage of 3BP2 in dectin-1-stimulated BMDCs. Finally, we identified hematopoietic cell-specific Lyn substrate 1 as a target of 3BP2, which is essential for dectin-1-induced expression of interleukin 10 in BMDCs. These results indicate that 3BP2 regulates gene expression and functions of MALT1 in dectin-1-stimulated cells and that 3BP2 plays an important role in the dectin-1-mediated antifungal immunity.

中文翻译：

---

在 dectin-1 刺激的细胞中，除了 MALT1 的泛素化和蛋白水解活性外，接头蛋白 3BP2 还调节基因表达。


Dectin-1 是一种 C 型凝集素，在诱导抗真菌免疫中起重要作用。包含 Caspase 募集结构域的蛋白 9 （CARD9） 对于通过 NF-κB 激活诱导的 dectin-1 诱导的细胞因子产生至关重要。然而，dectin-1 介导的 CARD9 激活的分子机制尚未完全阐明。最近，我们报道了衔接蛋白 SH3 结构域结合蛋白 2 （3BP2） 是 dectin-1 诱导的细胞因子产生和 NF-κB 激活所必需的，尽管 dectin-1 介导的信号传导中 3BP2 和 CARD9 之间的关系仍不清楚。在这里，我们报道了 3BP2 是 dectin-1 诱导的几个基因表达所必需的，这些基因可能有助于骨髓来源的树突状细胞 （BMDC） 中的抗真菌免疫。使用 HEK-293T 细胞的报告基因测定结果表明，3BP2 通过 B 细胞白血病/淋巴瘤 10、粘膜相关淋巴组织淋巴瘤易位蛋白 1 （MALT1） 和 TNF 受体相关因子 6 依赖性机制诱导 CARD9 介导的 NF-κB 激活。此外，我们表明 3BP2 诱导 CARD9 介导的细胞蛋白泛素化，并且 MALT1 以 CARD9 依赖性方式切割 3BP2。此外，我们表明，除了激活之外，MALT1 的泛素化还需要 3BP2，这导致 12tin-1 刺激的 BMDC 中 3BP2 的 MALT1 独立切割。最后，我们确定造血细胞特异性 Lyn 底物 1 是 3BP2 的靶标，这对于 dectin-1 诱导的白细胞介素 10 在 BMDC 中的表达至关重要。这些结果表明，3BP2 调节 dectin-1 刺激细胞中 MALT1 的基因表达和功能，并且 3BP2 在 dectin-1 介导的抗真菌免疫中起重要作用。