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LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission

Author

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  • Pei Wang

    (Stanford University, 240 Pasteur Drive)

  • Katharine K. Miller

    (Stanford University, 240 Pasteur Drive)

  • Enqi He

    (Stanford University, 240 Pasteur Drive)

  • Siddhant S. Dhawan

    (Stanford University, 240 Pasteur Drive)

  • Christopher L. Cunningham

    (University of Pittsburgh)

  • Nicolas Grillet

    (Stanford University, 240 Pasteur Drive)

Abstract

Hair cell bundles consist of stereocilia arranged in rows of increasing heights, connected by tip links that transmit sound-induced forces to shorter stereocilia tips. Auditory mechanotransduction channel complexes, composed of proteins TMC1/2, TMIE, CIB2, and LHFPL5, are located at the tips of shorter stereocilia. While most components can interact with the tip link in vitro, their ability to maintain the channel complexes at the tip link in vivo is uncertain. Using mouse models, we show that an additional component, LOXHD1, is essential for keeping TMC1-pore forming subunits at the tip link but is dispensable for TMC2. Using SUB-immunogold-SEM, we showed that TMC1 localizes near the tip link but mislocalizes without LOXHD1. LOXHD1 selectively interacts with TMC1, CIB2, LHFPL5, and tip-link protein PCDH15. Our results demonstrate that TMC1-driven mature auditory channels require LOXHD1 to stay connected to the tip link and remain functional, while TMC2-driven developmental channels do not.

Suggested Citation

  • Pei Wang & Katharine K. Miller & Enqi He & Siddhant S. Dhawan & Christopher L. Cunningham & Nicolas Grillet, 2024. "LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51850-4
    DOI: 10.1038/s41467-024-51850-4
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    References listed on IDEAS

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    1. Katharine K. Miller & Pei Wang & Nicolas Grillet, 2024. "SUB-immunogold-SEM reveals nanoscale distribution of submembranous epitopes," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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