State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Elife. 2022 Nov 1;11:e80865. doi: 10.7554/eLife.80865.
Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of /, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.
非偏性遗传筛选提示了一些未被充分研究的基因在听力损失中发挥作用，这表明听觉功能所需的一些生物学过程仍有待探索。先前研究较少的基因 / 的缺失会导致小鼠耳聋，但它在听力中的作用尚不清楚。在这里，我们发现 缺失会导致斑马鱼耳聋。在 突变体中观察到机械转导缺陷、毛细胞的纤毛束变长变薄以及顶侧溶酶体增大。在培养的细胞中，Kiaa1024L/Minar2 主要定位于溶酶体，其过表达会募集胆固醇并增加胆固醇标记。引人注目的是，胆固醇在毛束膜中高度富集，而 缺失会减少胆固醇向毛束的定位。降低胆固醇水平会加重 突变体的毛细胞缺陷，而增加胆固醇水平则可以挽救 突变体的毛细胞缺陷。因此，胆固醇在毛束中起着至关重要的作用，而 Kiaa1024L/Minar2 调节胆固醇的分布和动态平衡，以确保正常的听力。
