<br>miR-669a-5p/G3BP/HDAC6/AKAP12 轴调节初级纤毛长度,Advanced Science

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miR-669a-5p/G3BP/HDAC6/AKAP12 轴调节初级纤毛长度
Advanced Science ( IF 14.3 ) Pub Date : 2023-12-13 , DOI: 10.1002/advs.202305068
Weina Wang ₁ , Xuyao Dai ₁ , Yue Li ₁ , Mo Li ₂ , Zongqi Chi ₂ , Xiaoyu Hu ₁ , Zhenshan Wang ₁

Affiliation

初级纤毛是大多数哺乳动物细胞中保守的细胞器，充当感知外部信号的“天线”。维持纤毛的生理长度是纤毛功能所必需的。 MicroRNA (miRNA) 是有效的基因表达调节因子，异常的 miRNA 表达与纤毛病密切相关。然而，miRNA 如何调节纤毛长度仍不清楚。在这里，使用钙休克方法和小 RNA 测序，鉴定出一种 miRNA，即 miR-669a-5p，它在富含纤毛的非细胞部分中高度表达。结果表明，miR-669a-5p 促进培养细胞中的纤毛伸长，但不促进纤毛形成。从机制上讲，miR-669a-5p 抑制 ras-GTP 酶激活蛋白 SH3 结构域结合蛋白 (G3BP) 的表达，从而抑制组蛋白脱乙酰酶 6 (HDAC6) 的表达，从而进一步上调 A 激酶锚定蛋白 12 (AKAP12)表达。这种效应最终会阻止纤毛分解并导致纤毛长度更长，可以通过上调 HDAC6 或下调 AKAP12 将纤毛长度恢复到野生型长度。总的来说，这些结果阐明了之前未知的调节纤毛长度的 miR-669a-5p/G3BP/HDAC6/AKAP12 信号通路，为治疗纤毛病提供了潜在的药物靶点。

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The miR-669a-5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length

Primary cilia are conserved organelles in most mammalian cells, acting as “antennae” to sense external signals. Maintaining a physiological cilium length is required for cilium function. MicroRNAs (miRNAs) are potent gene expression regulators, and aberrant miRNA expression is closely associated with ciliopathies. However, how miRNAs modulate cilium length remains elusive. Here, using the calcium-shock method and small RNA sequencing, a miRNA is identified, namely, miR-669a-5p, that is highly expressed in the cilia-enriched noncellular fraction. It is shown that miR-669a-5p promotes cilium elongation but not cilium formation in cultured cells. Mechanistically, it is demonstrated that miR-669a-5p represses ras-GTPase-activating protein SH3-domain-binding protein (G3BP) expression to inhibit histone deacetylase 6 (HDAC6) expression, which further upregulates A-kinase anchor protein 12 (AKAP12) expression. This effect ultimately blocks cilia disassembly and leads to greater cilium length, which can be restored to wild-type lengths by either upregulating HDAC6 or downregulating AKAP12. Collectively, these results elucidate a previously unidentified miR-669a-5p/G3BP/HDAC6/AKAP12 signaling pathway that regulates cilium length, providing potential pharmaceutical targets for treating ciliopathies.

更新日期：2023-12-13

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