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Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility

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Listed:
  • Haoting Wang

    (Osaka University
    Osaka University)

  • Keisuke Shimada

    (Osaka University
    Rakuno Gakuen University)

  • Anh Hoang Pham

    (Osaka University
    Osaka University)

  • Yuki Oyama

    (Osaka University
    Osaka University
    Helmholtz Munich)

  • Maki Kamoshita

    (Osaka University
    Azabu University)

  • Hiroko Kobayashi

    (Osaka University
    Osaka University
    Kyoto University)

  • Seiya Oura

    (Osaka University
    Osaka University
    University of Texas Southwestern Medical Center)

  • Norikazu Yabuta

    (Osaka University)

  • Masahito Ikawa

    (Osaka University
    Osaka University
    The University of Tokyo
    Osaka University)

  • Haruhiko Miyata

    (Osaka University)

Abstract

Radial spokes (RSs) are conserved multimolecular structures attached to the axonemal microtubule doublets and are essential for the motility control of both cilia and sperm flagella. CFAP91, an RS3 protein, is implicated in human male infertility, yet its molecular function remains poorly understood. Here, we demonstrate that Cfap91 knockout (KO) mice exhibit impaired sperm flagellum formation and male infertility. Using a transgenic rescue model expressing FLAG- and BioID2-tagged CFAP91, we reveal that CFAP91 immunoprecipitates with RS3 proteins CFAP251 and LRRC23, whose localization is disrupted in Cfap91 KO sperm flagella. In addition, proximity labeling in mature spermatozoa identifies EFCAB5 as a sperm-specific CFAP91-proximal component. We show that Efcab5 KO males exhibit reduced sperm motility and fertility. Our findings establish CFAP91 as an essential scaffolder of RS3 assembly and EFCAB5 as a sperm-specialized movement regulator, advancing understanding of axonemal specialization in mammalian spermatozoa and its relevance to male infertility.

Suggested Citation

  • Haoting Wang & Keisuke Shimada & Anh Hoang Pham & Yuki Oyama & Maki Kamoshita & Hiroko Kobayashi & Seiya Oura & Norikazu Yabuta & Masahito Ikawa & Haruhiko Miyata, 2025. "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63705-7
    DOI: 10.1038/s41467-025-63705-7
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