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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 \u03b3-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\u2013bacterial stimulation, respectively. Moreover, the shedding signal then mediated Dscam with an intact cytoplasmic domain to promote the cleavage of ICDs by \u03b3-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.<\/jats:p>","DOI":"10.4049\/jimmunol.2100575","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T16:20:46Z","timestamp":1632759646000},"page":"2265-2277","source":"Crossref","is-referenced-by-count":23,"title":["Down Syndrome Cell Adhesion Molecule Triggers Membrane-to-Nucleus Signaling\u2013Regulated Hemocyte Proliferation against Bacterial Infection in Invertebrates"],"prefix":"10.1093","volume":"207","author":[{"given":"Hao","family":"Li","sequence":"first","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-1621","authenticated-orcid":false,"given":"Xing-Kun","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Marine Biology, College of Oceanography, Hohai University , Nanjing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7215-6571","authenticated-orcid":false,"given":"Kai-Min","family":"Zhou","sequence":"additional","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Hong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-7692","authenticated-orcid":false,"given":"Qun","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-2417","authenticated-orcid":false,"given":"Wei-Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Invertebrate Immunological Defense & Reproductive Biology, School of Life Sciences, East China Normal University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,1]]},"reference":[{"key":"2025022610322098400_r1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/ng0102-13","article-title":"A genomic view of alternative splicing","volume":"30","author":"Modrek","year":"2002","journal-title":"Nat. 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