2025-10-15 大阪大学微生物病研究所
図1)TMEM217とcAMP産生
TMEM217はSLC9C1というタンパク質と協働してcAMP産生タンパク質(sAC)を安定に保っている。
<関連情報>
- https://www.biken.osaka-u.ac.jp/achievement/research/2025/248
- https://www.biken.osaka-u.ac.jp/_files/_ck/files/researchtopics/2025/2025IidaMiyataIkawa_PNAS_web.pdf
TMEM217とナトリウム-プロトン交換輸送体SLC9C1との複合体の形成は、マウスの精子の運動性と雄の生殖能力に重要である Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility
Rie Iida-Norita, Haruhiko Miyata, Akinori Ninomiya, +4 , and Masahito Ikawa
Proceedings of the National Academy of Sciences Published:October 15, 2025
DOI:https://doi.org/10.1073/pnas.2513924122
Significance
Asthenozoospermia, characterized by impaired sperm motility, is a common cause of male infertility. The Na+/H+ exchanger SLC9C1 is a critical regulator of sperm motility through the modulation of intracellular signaling. In this study, we demonstrate that TMEM217 is an interaction partner of SLC9C1. Our results indicate that the TMEM217–SLC9C1 complex is essential for 3′,5′-cyclic monophosphate (cAMP) signaling, sperm motility, and male fertility. Importantly, impaired sperm motility and fertilization ability of Tmem217 Knockout (KO) spermatozoa were rescued by enhancing cAMP signaling. Our findings reveal the biological significance of the conserved TMEM217–SLC9C1 interaction and give insights into the diagnosis and therapeutic strategy of asthenozoospermia associated with defective cAMP signaling.
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.
