Belyantseva Inna A, Liu Chang, Dragich Abigail K, Miyoshi Takushi, Inagaki Sayaka, Imtiaz Ayesha, Tona Risa, Zuluaga-Osorio Karen Sofia, Hadi Shadan, Wilson Elizabeth, Morozko Eva, Olszewski Rafal, Yousaf Rizwan, Sokolova Yuliya, Riordan Gavin P, Aston S Andrew, Rehman Atteeq U, Fenollar Ferrer Cristina, Wisniewski Jan, Gu Shoujun, Nayak Gowri, Goodyear Richard J, Li Jinan, Krey Jocelyn F, Wafa Talah, Faridi Rabia, Adadey Samuel Mawuli, Drummond Meghan, Perrin Benjamin, Winkler Dennis C, Starost Matthew F, Cheng Hui, Fitzgerald Tracy, Richardson Guy P, Dong Lijin, Barr-Gillespie Peter G, Hoa Michael, Frolenkov Gregory I, Friedman Thomas B, Zhao Bo
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
J Cell Biol. 2025 Aug 4;224(8). doi: 10.1083/jcb.202408026. Epub 2025 Jun 5.
Stereocilia are rod-like mechanosensory projections consisting of unidirectionally oriented actin filaments that extend into the inner ear hair cell cytoskeleton, forming dense rootlets. Taperin (TPRN) localizes to the narrowed-down base of stereocilia, where they pivot in response to sound and gravity. We show that TPRN-deficient mice have progressive deafness characterized by gradual asynchronous retraction and fusion of outer and inner hair cell stereocilia, followed by synaptic abnormalities. Stereocilia that lack TPRN develop warped rootlets with gradual loss of TRIOBP-5 and ANKRD24 from mechanosensory rows starting postnatally. In contrast, TPRN overexpression causes excessive F-actin bundling, extra rows, and over-elongation of stereocilia during development. Purified full-length mouse TPRN cross-links F-actin into bendable bundles reflecting in vivo data. This F-actin-bundling ability is attributed to the TPRN N-terminal region. TPRN interacts with the membrane receptor PTPRQ, connecting the F-actin core to the plasma membrane, stabilizing stereocilia. Thus, TPRN is a specialized F-actin bundler strategically located to augment stereocilia rootlet formation and their pivot point flexibility for sustained sound-induced deflections.
静纤毛是棒状的机械感觉突起，由单向排列的肌动蛋白丝组成，这些肌动蛋白丝延伸到内耳毛细胞的细胞骨架中，形成致密的小根。Taperin（TPRN）定位于静纤毛变窄的基部，静纤毛在此处响应声音和重力而发生枢转。我们发现，缺乏TPRN的小鼠患有进行性耳聋，其特征是外毛细胞和内毛细胞静纤毛逐渐异步回缩和融合，随后出现突触异常。缺乏TPRN的静纤毛会形成扭曲的小根，从出生后开始，机械感觉排中的TRIOBP-5和ANKRD24会逐渐丢失。相反，TPRN的过表达会导致发育过程中F-肌动蛋白过度成束、额外的排以及静纤毛过度伸长。纯化的全长小鼠TPRN将F-肌动蛋白交联成可弯曲的束，这与体内数据相符。这种F-肌动蛋白成束能力归因于TPRN的N端区域。TPRN与膜受体PTPRQ相互作用，将F-肌动蛋白核心与质膜连接起来，稳定静纤毛。因此，TPRN是一种特殊的F-肌动蛋白成束蛋白，其定位策略性地增强了静纤毛小根的形成及其枢轴点的灵活性，以维持声音引起的持续偏转。
