Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab
Alternatively spliced down syndrome cell adhesion molecule (Dscam) controls innate immunity in crab
复制标题
选择性剪接唐氏综合症细胞粘附分子（Dscam）控制螃蟹的先天免疫
DOI：
10.1074/jbc.ra119.010247
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发表时间：
2019-11-01
影响因子：
4.8
通讯作者：
Li, Weiwei
中科院分区：
文献类型：
--
作者：
Li, Dan;Wan, Zhicheng;Li, Weiwei
选择性剪接的高变免疫球蛋白结构域编码分子，称为唐氏综合征细胞粘附分子（Dscam），已被广泛检测到作为节肢动物免疫系统的组成部分。虽然它的能力，特异性结合病原体，使吞噬细菌已阐明，信号转导机制或效应，激活后Dscam？结合病原体的特征仍然很差。在此，我们揭示了中华绒螯蟹（Eriocheir sinensis）血细胞中Dscam的胞质尾区及其亚型的选择性剪接外显子，表明Dscam的表达在免疫攻击后被急性诱导，这表明其在先天免疫中起作用。在体外检测到Dscam沉默的蟹血细胞中抗菌分子肽（AMP）的表达水平显著降低，这与它们对金黄色葡萄球菌的易感性和体内发生的较高细菌浓度相一致。进一步的实验研究表明，Dscam调节AMP的表达，通过Src同源性（SH）3-结合结构域中的第一个恒定外显子翻译蛋白质的细胞质尾结合SH 3结构域的码头，SH 3/SH 2衔接蛋白轴突的指导。Dock通过间接结合促进细胞外信号调节激酶（ERK）磷酸化，然后调节背侧磷酸化和从细胞质易位到细胞核，随后促进AMP表达以有效去除细菌。据我们所知，这项全面的研究是第一次强调选择性剪接的Dscam细胞质尾区在抗菌控制活性中的关键作用。这也表明Dscam和其他模式识别受体之间可能发生串扰。
Alternatively-spliced hypervariable immunoglobulin domain-encoding molecules, called Down syndrome cell adhesion molecule (Dscam), have been widely detected as components of the arthropod immune system. Although its ability to specifically bind pathogens and enable phagocytosis of bacteria has been elucidated, the signal transduction mechanisms or effectors that activate post-Dscam?binding pathogens remain poorly characterized. Here, we reveal the alternative splicing exons of Dscam's cytoplasmic tail and its isoforms in the hemocytes of crab (Eriocheir sinensis), showing that the expression of Dscam was acutely induced after an immune challenge, which suggested its functioning for innate immunity. Significantly decreased expression levels of antimicrobial molecular peptides (AMPs) were detected in Dscam-silenced crab hemocytes in vitro, which coincided with their vulnerability to infection by Staphylococcus aureus and higher bacterial concentrations occurring in Dscam-silenced crabs in vivo. Further experimental investigation demonstrated that Dscam-regulated AMP expression via the Src homology (SH)3-binding domain in the first constant exon translated protein of the cytoplasmic tail bound with the SH3 domain of the Dock, an SH3/SH2 adaptor protein required for axon guidance. Dock promoted extracellular signal-regulated kinase (ERK) phosphorylation via indirect binding and then regulated dorsal phosphorylation and translocation from the cytoplasm to the nucleus, subsequently promoting AMP expression for the effective removal of bacteria. To the best of our knowledge, this comprehensive study is the first to highlight the critical role of the alternatively-spliced Dscam cytoplasmic tail in antimicrobial control activity. It also suggests possible cross-talk occurring between Dscam and other pattern recognition receptors.