Down Syndrome Cell Adhesion Molecule Triggers Membrane-to-Nucleus Signaling–Regulated Hemocyte Proliferation against Bacterial Infection in Invertebrates
Down Syndrome Cell Adhesion Molecule Triggers Membrane-to-Nucleus Signaling–Regulated Hemocyte Proliferation against Bacterial Infection in Invertebrates
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DOI：
10.4049/jimmunol.2100575
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Hao Li;Xingkun Jin;Kaimin Zhou;Hui Zhao;Yue Zhao;Qun Wang;Weiwei Li
中科院分区：
文献类型：
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作者：
Hao Li;Xingkun Jin;Kaimin Zhou;Hui Zhao;Yue Zhao;Qun Wang;Weiwei Li
关键点蛋白酶ADAM 10在细菌感染时切割Dscam的胞外域。IPO 5结合并将Dscam胞内结构域从细胞质易位到细胞核中。核导入Dscam调节血细胞增殖。唐氏综合征细胞粘附分子（Dscam）通过选择性剪接产生数万种异构体，从而在免疫应答期间提供关键功能。在这项研究中，一个新的Dscam信号通路的研究在螃蟹，这仍然是在无脊椎动物的特点。细菌感染诱导Dscam胞内结构域（ICDs）被γ-分泌酶裂解，释放的ICDs携带特异性可变剪接外显子，可直接与IPO 5相互作用，促进核转位。因此，核输入ICD促进血细胞增殖并保护宿主免受细菌感染。蛋白质相互作用的研究表明，Dscam的胞外域结合到一个解整合素和金属蛋白酶结构域10（ADAM 10），而不是ADAM 17。ADAM 10的抑制或过度表达分别损害或加速细菌刺激后的Dscam脱落活性。此外，脱落信号然后介导具有完整胞质结构域的Dscam，以促进γ-分泌酶对ICD的切割。此外，ADAM 10的转录受Dscam诱导的经典信号的调节，而不是核输入的ICD，作为两个不同的Dscam途径之间的反馈调节。因此，Dscam的膜到核信号传导调节血细胞增殖以响应细菌感染。
Key Points Protease ADAM10 cleaves the ectodomain of Dscam upon bacterial infection. IPO5 binds and translocates Dscam intracellular domains from cytoplasm into nuclei. Nuclear imported Dscam regulates hemocytes proliferation. Down syndrome cell adhesion molecule (Dscam) generates tens of thousands of isoforms by alternative splicing, thereby providing crucial functions during immune responses. In this study, a novel Dscam signaling pathway was investigated in crab, which remains poorly characterized in invertebrates. Bacterial infection induced the cytoplasmic cleavage of Dscam intracellular domains (ICDs) by γ-secretase, and then the released ICDs carrying specific alternatively spliced exons could directly interact with IPO5 to facilitate nuclear translocation. Nuclear imported ICDs thus promoted hemocyte proliferation and protect the host from bacterial infection. Protein-interaction studies revealed that the ectodomain of Dscam bound to a disintegrin and metalloprotease domain 10 (ADAM10) rather than ADAM17. Inhibition or overexpression of ADAM10 impaired or accelerated Dscam shedding activity post–bacterial stimulation, respectively. Moreover, the shedding signal then mediated Dscam with an intact cytoplasmic domain to promote the cleavage of ICDs by γ-secretase. Furthermore, the transcription of ADAM10 was regulated by Dscam-induced canonical signaling, but not nuclear imported ICDs, to serve as a feedback regulation between two different Dscam pathways. Thus, membrane-to-nuclear signaling of Dscam regulated hemocyte proliferation in response to bacterial infection.