Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility

Iida-Norita, Rie; Miyata, Haruhiko; Ninomiya, Akinori; Emori, Chihiro; Kamoshita, Maki; Pan, Chen; Wang, Haoting; Ikawa, Masahito

doi:https://doi.org/10.1073/pnas.2513924122

Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility

Iida-Norita, Rie; Miyata, Haruhiko; Ninomiya, Akinori et al.

Proceedings of the National Academy of Sciences of the United States of America, 2025, 122(42), e2513924122

Number of Access:22（2026-02-05 22:23 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/103682

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Title	Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility
Creator	NRID 1000010816771 1000010816771 ORCID 0000-0003-0104-1974 0000-0003-0104-1974 researchmap permalink 7000029591 7000029591 Scopus Author ID 57209731748 57209731748 CreatorName Iida-Norita, Rie
	NRID 1000050604732 1000050604732 ORCID 0000-0003-4758-5803 0000-0003-4758-5803 researchmap permalink hmiyata hmiyata Scopus Author ID 37161837000 37161837000 CreatorName Miyata, Haruhiko
	ORCID 0000-0001-6133-3835 0000-0001-6133-3835 researchmap permalink a_ninomiya a_ninomiya Scopus Author ID 57214867090 57214867090 CreatorName Ninomiya, Akinori
	NRID 1000010868136 1000010868136 ORCID 0000-0001-8040-2517 0000-0001-8040-2517 researchmap permalink cemori cemori Scopus Author ID 55937469900 55937469900 CreatorName Emori, Chihiro
	NRID 1000070930288 1000070930288 ORCID 0009-0009-7853-5164 0009-0009-7853-5164 researchmap permalink m.kamoshita m.kamoshita Scopus Author ID 55642236500 55642236500 CreatorName Kamoshita, Maki
	CreatorName Pan, Chen
	CreatorName Wang, Haoting
	NRID 1000020304066 1000020304066 ORCID 0000-0001-9859-6217 0000-0001-9859-6217 researchmap permalink read0054910 read0054910 Scopus Author ID 16689054500 16689054500 CreatorName Ikawa, Masahito
Subject	cAMP signaling
	male fertility
	sodium-proton exchanger
	sperm motility
	therapy for infertility
Description	Iida-Norita R., Miyata H., Ninomiya A., et al. Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. Proceedings of the National Academy of Sciences of the United States of America 122, e2513924122 (2025); https://doi.org/10.1073/pnas.2513924122.
Abstract	Sperm motility is essential for male fertility and is tightly controlled by signaling events in the flagellum. Slc9c1 encodes a sperm-specific Na⁺/H⁺ exchanger (sNHE/SLC9C1) that localizes to the flagellum and is indispensable for sperm motility and male fertility. SLC9C1 is unique among Na⁺/H⁺ 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 Slc9c1, we identified Tmem217, which encodes a transmembrane protein that is localized in the sperm flagellum. Knockout (KO) of Tmem217 in mice resulted in sperm motility defects and male infertility, phenocopying Slc9c1 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 Tmem217 KO spermatozoa, leading to disrupted 3′,5′-cyclic monophosphate (cAMP) signaling pathways. Remarkably, cAMP analogs restored the impaired motility and fertilizing ability of Tmem217 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–sAC–cAMP axis in mature spermatozoa.
Publisher	National Academy of Sciences
Source Title	Proceedings of the National Academy of Sciences of the United States of America
Volume (Issue)	122(42)
Page	e2513924122
Date of Issued	2025-10-15
Language	English
Handle URL	https://hdl.handle.net/11094/103682
PISSN	00278424
eISSN	10916490
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1073/pnas.2513924122
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Proceedings of the National Academy of Sciences of the United States of America. 2025, 122(42), p. e2513924122
DC.title	Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility
DC.creator	Iida-Norita, Rie
	Miyata, Haruhiko
	Ninomiya, Akinori
	Emori, Chihiro
	Kamoshita, Maki
	Pan, Chen
	Wang, Haoting
	Ikawa, Masahito
DC.publisher	National Academy of Sciences
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-15
DC.identifier	https://doi.org/10.1073/pnas.2513924122
DC.subject	cAMP signaling
	male fertility
	sodium-proton exchanger
	sperm motility
	therapy for infertility
DC.description	Iida-Norita R., Miyata H., Ninomiya A., et al. Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. Proceedings of the National Academy of Sciences of the United States of America 122, e2513924122 (2025); https://doi.org/10.1073/pnas.2513924122.
DCTERMS.abstract	Sperm motility is essential for male fertility and is tightly controlled by signaling events in the flagellum. Slc9c1 encodes a sperm-specific Na⁺/H⁺ exchanger (sNHE/SLC9C1) that localizes to the flagellum and is indispensable for sperm motility and male fertility. SLC9C1 is unique among Na⁺/H⁺ 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 Slc9c1, we identified Tmem217, which encodes a transmembrane protein that is localized in the sperm flagellum. Knockout (KO) of Tmem217 in mice resulted in sperm motility defects and male infertility, phenocopying Slc9c1 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 Tmem217 KO spermatozoa, leading to disrupted 3′,5′-cyclic monophosphate (cAMP) signaling pathways. Remarkably, cAMP analogs restored the impaired motility and fertilizing ability of Tmem217 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–sAC–cAMP axis in mature spermatozoa.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103682
citation_title	Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility
citation_author	Iida-Norita, Rie
	Miyata, Haruhiko
	Ninomiya, Akinori
	Emori, Chihiro
	Kamoshita, Maki
	Pan, Chen
	Wang, Haoting
	Ikawa, Masahito
citation_publisher	National Academy of Sciences
citation_language	English
citation_date	2025-10-15
citation_journal_title	Proceedings of the National Academy of Sciences of the United States of America
citation_volume	122
citation_issue	42
citation_firstpage	e2513924122
citation_doi	https://doi.org/10.1073/pnas.2513924122
citation_public_url	https://hdl.handle.net/11094/103682

Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility

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