Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
Department of Medicine Statistics Core, University of California, Los Angeles, California 90095, United States.
ACS Chem Biol. 2024 Aug 16;19(8):1733-1742. doi: 10.1021/acschembio.4c00186. Epub 2024 Aug 6.
Primary cilia are membrane-covered microtubule-based structures that protrude from the cell surface and are critical for cell signaling and homeostasis during human development and adulthood. Dysregulation of cilia formation, length, and function can lead to a spectrum of human diseases and syndromes known as ciliopathies. Although some genetic and chemical screens have been performed to define important factors that modulate cilia biogenesis and length control, there are currently no clinical treatments that restore cilia length in patients. We report that the microtubule-targeting agent MI-181(mitotic inhibitor-181) is a potent modulator of cilia length and biogenesis. Treatment of retinal pigment epithelial-1 cells with MI-181 induced an increase in the average size of cilia and in the percent ciliated cells under nonstarved conditions. Importantly, MI-181 was effective at rescuing cilia length and ciliation defects in cells that had been treated with the intraflagellar transport inhibitor Ciliobrevin D or the O-GlcNAc transferase inhibitor OSMI-1. Most importantly, MI-181 induced an increase in cilia length and restored ciliation in cells with compromised shortened cilia at low nanomolar concentrations and did not show an inhibitory response at high concentrations. Therefore, MI-181 represents a lead molecule for developing drugs targeting ciliopathies characterized by shortened cilia.
原发性纤毛是一种从细胞表面突出的、由膜覆盖的微管为基础的结构，对于人类发育和成年过程中的细胞信号转导和内稳态至关重要。纤毛形成、长度和功能的失调会导致一系列被称为纤毛病的人类疾病和综合征。尽管已经进行了一些遗传和化学筛选，以确定调节纤毛发生和长度控制的重要因素，但目前尚无临床治疗方法可以恢复患者的纤毛长度。我们报告说，微管靶向药物 MI-181（有丝分裂抑制剂-181）是纤毛长度和发生的有效调节剂。用 MI-181 处理视网膜色素上皮-1 细胞会导致非饥饿条件下纤毛的平均大小和纤毛细胞的比例增加。重要的是，MI-181 可以有效挽救已用鞭毛内运输抑制剂 Ciliobrevin D 或 O-GlcNAc 转移酶抑制剂 OSMI-1 处理的细胞中的纤毛长度和纤毛缺陷。最重要的是，MI-181 以低纳摩尔浓度诱导纤毛长度增加，并恢复了纤毛缩短的细胞中的纤毛化，而在高浓度下没有抑制反应。因此，MI-181 代表了一种针对以纤毛缩短为特征的纤毛病的药物开发的先导分子。
