Department of Otolaryngology-Head and Neck Surgery, Stanford University, 240 Pasteur Drive, Stanford, CA, USA.
Pittsburgh Hearing Research Center, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Nat Commun. 2024 Sep 10;15(1):7865. doi: 10.1038/s41467-024-51850-4.
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. Return, 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.
毛细胞束由排列成递增高度的纤毛组成，纤毛通过连接较短纤毛尖端的连接梢传递声音引起的力。听觉机械转导通道复合物由 TMC1/2、TMIE、CIB2 和 LHFPL5 等蛋白组成，位于较短纤毛的尖端。虽然大多数成分可以在体外与连接梢相互作用，但它们在体内维持通道复合物在连接梢上的能力尚不确定。在小鼠模型中，我们发现另一个组件 LOXHD1 对于将 TMC1-孔形成亚基保持在连接梢上是必不可少的，但对于 TMC2 则是可有可无的。使用 SUB-免疫金-SEM，我们发现 TMC1 定位于连接梢附近，但在没有 LOXHD1 的情况下会发生定位错误。LOXHD1 选择性地与 TMC1、CIB2、LHFPL5 和连接梢蛋白 PCDH15 相互作用。我们的结果表明，TMC1 驱动的成熟听觉通道需要 LOXHD1 与连接梢保持连接并保持功能，而 TMC2 驱动的发育通道则不需要。
