Identification of Regulators for Ciliary Disassembly by a Chemical Screen.
Identification of Regulators for Ciliary Disassembly by a Chemical Screen.
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DOI：
10.1021/acschembio.1c00823
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发表时间：
2021-11
影响因子：
4
通讯作者：
Zhijun Dong;Jia Xu;Junmin Pan
中科院分区：
文献类型：
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作者：
Zhijun Dong;Jia Xu;Junmin Pan
纤毛是细胞信号传导和运动的细胞器。它们在 G0/G1 中组装并在有丝分裂前分解。与对纤毛组装的了解相比，对纤毛分解的了解较少。为了揭示纤毛分解的新机制，我们进行了公正的化学筛选。通过焦磷酸钠处理，实验性地诱导莱茵衣藻细胞纤毛分解。 FDA 批准的药物库（HY-L022P-1，MedChemExpress）用于筛选。初步筛选和进一步实验已确定微管稳定剂紫杉烷、CDK4/6 抑制剂 abemaciclib 和 Raf 抑制剂 dabrafenib 可有效抑制实验诱导的纤毛解体，而且在生理条件下也能有效抑制纤毛解体。此外，它们对哺乳动物细胞中纤毛分解的影响也已得到证实。因此，我们的研究不仅揭示了纤毛分解的新机制，而且为研究纤毛分解提供了新的工具。这些发现的药物可用于涉及纤毛变性的疾病（例如视网膜病）的治疗干预。
Cilia are organelles for cellular signaling and motility. They are assembled in G0/G1 and disassembled prior to mitosis. Compared to what is known about ciliary assembly, less is understood about ciliary disassembly. To uncover new mechanisms of ciliary disassembly, we performed an unbiased chemical screen. Chlamydomonas reinhardtii cells were experimentally induced for ciliary disassembly by treatment with sodium pyrophosphate. An FDA approved drug library (HY-L022P-1, MedChemExpress) was used for the screening. Primary screening with further experiments has identified microtubule stabilizer taxanes, CDK4/6 inhibitor abemaciclib and Raf inhibitor dabrafenib being effective in inhibiting ciliary disassembly induced experimentally but also under physiological conditions. In addition, their effects on ciliary disassembly in mammalian cells has also been confirmed. Thus, our studies have not only revealed new mechanisms in ciliary disassembly but also provided new tools for studying ciliary disassembly. These discovered drugs may be used for therapeutic interventions of disorders involving ciliary degeneration such as retinopathies.