{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:18:46Z","timestamp":1787854726505,"version":"build-2784847793"},"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006559","name":"University of Tsukuba","doi-asserted-by":"crossref","award":["202403; 202505"],"award-info":[{"award-number":["202403; 202505"]}],"id":[{"id":"10.13039\/501100006559","id-type":"DOI","asserted-by":"crossref"}]},{"name":"PMAC Science Research Promotion Fund"},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19K06448"],"award-info":[{"award-number":["JP19K06448"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Exocytotic sperm remodeling is essential for fertilization, yet whether conserved molecular mechanisms underlie this process across species remains unclear. In\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , membranous organelle fusion (MOF), an exocytotic event cytologically analogous to the mammalian acrosome reaction (ASR), occurs during spermiogenesis and likely contributes to the acquisition of fertilization competence. Here, we identify DDI-4, a benzylamine analog as a small-molecule inducer of both MOF and ASR, revealing a shared sensitivity between these evolutionarily distant systems. DDI-4\u2013induced MOF was selectively impaired in spermatids from males raised at elevated temperatures, whereas conventional protease\u2013induced MOF remained unaffected. Through forward genetics, we isolated the\n                    <jats:italic>nyg20<\/jats:italic>\n                    mutant, which was specifically defective in DDI-4 responsiveness. Complementation and genetic analyses suggested that the\n                    <jats:italic>nyg20<\/jats:italic>\n                    phenotype is associated with impaired function of\n                    <jats:italic>nsun-2<\/jats:italic>\n                    , encoding a tRNA methyltransferase, despite the absence of detectable mutations in the\n                    <jats:italic>nsun-2<\/jats:italic>\n                    coding, intronic, and flanking regions. Consistent with this, an\n                    <jats:italic>nsun-2<\/jats:italic>\n                    deletion mutant exhibited defects in temperature-sensitive MOF and meiosis.\n                    <jats:italic>In silico<\/jats:italic>\n                    docking analysis further implicated sphingosine kinases (SPHKs) as candidate targets of DDI-4; indeed, loss of\n                    <jats:italic>sphk-1<\/jats:italic>\n                    phenocopied the\n                    <jats:italic>nsun-2<\/jats:italic>\n                    mutant. Moreover, we tested sphingosine (SPH) and its analog FTY720 as MOF activators, using mutants lacking\n                    <jats:italic>sphk-1<\/jats:italic>\n                    or\n                    <jats:italic>spin-4<\/jats:italic>\n                    , which encodes a transporter of phosphorylated SPH. Intriguingly, DDI-4 and SPH activated MOF in an SPHK-1\u2013dependent but SPIN-4\u2013independent manner, whereas FTY720 required both SPHK-1 and SPIN-4 for MOF activation. Because DDI-4 lacks hydroxyl groups that SPHKs typically phosphorylate, these findings suggest that SPHK-1 may function not only as a kinase but also as a scaffold for downstream signaling. Together, our results reveal a temperature-sensitive, NSUN-2\u2013dependent SPH-mediated signaling axis that regulates organelle exocytosis during spermiogenesis and suggest an evolutionarily conserved mechanism underlying fertilization competence.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012275","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T17:28:01Z","timestamp":1787851681000},"page":"e1012275","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["DDI-4 induces a temperature-sensitive exocytotic remodeling during C. elegans spermiogenesis via nsun-2\u2013dependent sphingosine signaling"],"prefix":"10.1371","volume":"22","author":[{"given":"Yoshihiro","family":"Shimada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riona","family":"Shiraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Kanazawa-Takino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2106-3399","authenticated-orcid":true,"given":"Yukiko","family":"Karuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-0558","authenticated-orcid":true,"given":"Kentaro","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaharu","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arata","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-0999","authenticated-orcid":true,"given":"Jun-Dal","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiyoshi","family":"Fukamizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1210-1768","authenticated-orcid":true,"given":"Masaaki","family":"Omote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5068-1738","authenticated-orcid":true,"given":"Hitoshi","family":"Nishimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"pgen.1012275.ref001","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/B978-0-12-397175-3.00003-X","article-title":"The 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