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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"<jats:p>\n                    Sperm motility is essential for male fertility and is tightly controlled by signaling events in the flagellum.\n                    <jats:italic toggle=\"yes\">Slc9c1<\/jats:italic>\n                    encodes a sperm-specific Na\n                    <jats:sup>+<\/jats:sup>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    exchanger (sNHE\/SLC9C1) that localizes to the flagellum and is indispensable for sperm motility and male fertility. SLC9C1 is unique among Na\n                    <jats:sup>+<\/jats:sup>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    exchangers in that it possesses a voltage-sensing domain (VSD), the physiological function of which remains poorly understood in mammals. Here, by analyzing coevolving genes with\n                    <jats:italic toggle=\"yes\">Slc9c1<\/jats:italic>\n                    , we identified\n                    <jats:italic toggle=\"yes\">Tmem217<\/jats:italic>\n                    , which encodes a transmembrane protein that is localized in the sperm flagellum. Knockout (KO) of\n                    <jats:italic toggle=\"yes\">Tmem217<\/jats:italic>\n                    in mice resulted in sperm motility defects and male infertility, phenocopying\n                    <jats:italic toggle=\"yes\">Slc9c1<\/jats:italic>\n                    KO mice. Coimmunoprecipitation and structural prediction analyses indicated that TMEM217 binds to SLC9C1 via its VSD. Further analyses indicated that the amounts of SLC9C1 and its associated protein, soluble adenylyl cyclase (sAC), were lost in mature\n                    <jats:italic toggle=\"yes\">Tmem217<\/jats:italic>\n                    KO spermatozoa, leading to disrupted 3\u2032,5\u2032-cyclic monophosphate (cAMP) signaling pathways. Remarkably, cAMP analogs restored the impaired motility and fertilizing ability of\n                    <jats:italic toggle=\"yes\">Tmem217<\/jats:italic>\n                    KO spermatozoa in vitro, validating the essential role of TMEM217 in regulating cAMP production. Our findings indicate that the association of TMEM217 with SLC9C1 via its VSD is critical for the proper organization and function of the SLC9C1\u2013sAC\u2013cAMP axis in mature spermatozoa.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513924122","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:39:33Z","timestamp":1760549973000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-1974","authenticated-orcid":false,"given":"Rie","family":"Iida-Norita","sequence":"first","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]},{"name":"Animal Resource Center for Infectious Diseases, Immunology Frontier Research Center, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4758-5803","authenticated-orcid":false,"given":"Haruhiko","family":"Miyata","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-3835","authenticated-orcid":false,"given":"Akinori","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Emori","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Kamoshita","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]},{"name":"Laboratory of Experimental Genome Research, Graduate School of Pharmaceutical Sciences, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5176-7170","authenticated-orcid":false,"given":"Haoting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]},{"name":"Laboratory of Experimental Genome Research, Graduate School of Pharmaceutical Sciences, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-6217","authenticated-orcid":false,"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka","place":["Suita, Osaka, Japan"]},{"name":"Animal Resource Center for Infectious Diseases, Immunology Frontier Research Center, The University of 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