TMEM145 is a principal component of outer hair cell stereocilia

The exquisite acuity of mammalian hearing relies on cochlear amplification provided by sensory outer hair cells (OHCs), downstream of mechanoelectrical transduction of sound. In OHCs, transduction is initiated by deflection of stereocilia conveyed through tethering to the tectorial membrane (TM) via an incompletely characterized protein complex, the TM attachment crowns (TM-ACs). We identify Tmem145, a G protein-coupled receptor (GPCR)-related "Golgi-dynamics-domain-seven-transmembrane (GOST)" protein, as the core element of TM-ACs. Tmem145 localized to the tips of the tallest row of stereocilia, precisely matching the localization of previously known components of TM-ACs, tubby, and stereocilin. Genetic ablation in mice resulted in loss of tubby and stereocilin from OHC stereocilia, disconnection of the hair bundle from the TM, and profound hearing loss with a lack of cochlear amplification. Tmem145 binds cytosolic tubby and anchors secreted stereocilin, likely through its extracellular Golgi-like domain. This architecture suggests a general role of Tmem145-related proteins as organizers of transmembrane anchor complexes.