State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
Cell Rep. 2021 Feb 23;34(8):108770. doi: 10.1016/j.celrep.2021.108770.
Stereocilia, the mechanosensory organelles on the apical surface of hair cells, are necessary to detect sound and carry out mechano-electrical transduction. An electron-dense matrix is located at the distal tips of stereocilia and plays crucial roles in the regulation of stereocilia morphology. Mutations of the components in this tip complex density (TCD) have been associated with profound deafness. However, the mechanism underlying the formation of the TCD is largely unknown. Here, we discover that the specific multivalent interactions among the Whirlin-myosin 15 (Myo15)-Eps8 complex lead to the formation of the TCD-like condensates through liquid-liquid phase separation. The reconstituted TCD-like condensates effectively promote actin bundling. A deafness-associated mutation of Myo15 interferes with the condensates formation and consequently impairs actin bundling. Therefore, our study not only suggests that the TCD in hair cell stereocilia may form via phase separation but it also provides important clues for the possible mechanism underlying hearing loss.
纤毛是毛细胞顶端表面的机械感受器器官，对于探测声音和进行机电转导是必需的。电子致密基质位于纤毛的远端尖端，在调节纤毛形态中发挥着关键作用。该尖端复合物密度（TCD）成分的突变与深度耳聋有关。然而，TCD 形成的机制在很大程度上尚不清楚。在这里，我们发现 Whirlin-肌球蛋白 15（Myo15）-Eps8 复合物之间的特定多价相互作用通过液-液相分离导致形成 TCD 样凝聚物。重建的 TCD 样凝聚物有效地促进了肌动蛋白的束集。Myo15 的一个耳聋相关突变干扰了凝聚物的形成，从而损害了肌动蛋白的束集。因此，我们的研究不仅表明毛细胞纤毛中的 TCD 可能通过相分离形成，而且为听力损失的可能机制提供了重要线索。
