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.

唐氏综合症细胞粘附分子 (Dscam) 通过选择性剪接产生数以万计的异构体，从而在免疫反应过程中提供关键功能。在这项研究中，在螃蟹中研究了一种新的 Dscam 信号通路，而螃蟹在无脊椎动物中的特征仍然很差。细菌感染通过 γ-分泌酶诱导 Dscam 胞内结构域 (ICD) 的细胞质裂解，然后释放的携带特定选择性剪接外显子的 ICD 可以直接与 IPO5 相互作用以促进核易位。因此，核输入 ICD 促进血细胞增殖并保护宿主免受细菌感染。蛋白质相互作用研究表明，Dscam 的胞外域与去整合素和金属蛋白酶结构域 10 (ADAM10) 而不是 ADAM17 结合。ADAM10 的抑制或过表达分别削弱或加速了细菌刺激后的 Dscam 脱落活动。此外，脱落信号随后介导具有完整细胞质结构域的 Dscam，以促进 γ-分泌酶对 ICD 的切割。此外，ADAM10 的转录受 Dscam 诱导的规范信号传导调节，但不受核输入 ICD 的调节，作为两种不同 Dscam 通路之间的反馈调节。因此，Dscam 的膜到核信号调节响应细菌感染的血细胞增殖。ADAM10 的转录受 Dscam 诱导的经典信号的调节，但不受核输入 ICD 的调节，作为两种不同 Dscam 通路之间的反馈调节。因此，Dscam 的膜到核信号调节响应细菌感染的血细胞增殖。ADAM10 的转录受 Dscam 诱导的经典信号的调节，但不受核输入 ICD 的调节，作为两种不同 Dscam 通路之间的反馈调节。因此，Dscam 的膜到核信号调节响应细菌感染的血细胞增殖。