TMC1 and TMC2 (TMC1/2) have been proposed to form the pore of the mechanotransduction channel of cochlear hair cells. Here, we show that TMC1/2 cannot form mechanotransduction channels in cochlear hair cells without TMIE. TMIE binds to TMC1/2, and a TMIE mutation that perturbs TMC1/2 binding abolishes mechanotransduction. N-terminal TMIE deletions affect the response of the mechanotransduction channel to mechanical force. Similar to mechanically gated TREK channels, the C-terminal cytoplasmic TMIE domain contains charged amino acids that mediate binding to phospholipids, including PIP₂. TMIE point mutations in the C terminus that are linked to deafness disrupt phospholipid binding, sensitize the channel to PIP₂ depletion from hair cells, and alter the channel’s unitary conductance and ion selectivity. We conclude that TMIE is a subunit of the cochlear mechanotransduction channel and that channel function is regulated by a phospholipid-sensing domain in TMIE with similarity to those in other mechanically gated ion channels.

TMC1 和 TMC2 (TMC1/2) 被提议形成耳蜗毛细胞的机械传导通道的孔。在这里，我们表明，如果没有 TMIE，TMC1/2 就无法在耳蜗毛细胞中形成机械转导通道。 TMIE 与 TMC1/2 结合，扰乱 TMC1/2 结合的 TMIE 突变会消除机械转导。 N 端 TMIE 缺失影响机械传导通道对机械力的响应。与机械门控 TREK 通道类似，C 端胞质 TMIE 结构域包含介导与磷脂（包括 PIP _{2 ）}结合的带电氨基酸。与耳聋相关的 C 末端 TMIE 点突变会破坏磷脂结合，使通道对毛细胞 PIP ₂消耗敏感，并改变通道的单一电导和离子选择性。我们得出结论，TMIE 是耳蜗机械转导通道的一个亚基，通道功能由 TMIE 中的磷脂感应结构域调节，与其他机械门控离子通道中的磷脂感应结构域相似。