TonEBP 通过控制 Aurora 激酶 A 和调节中心粒卫星完整性来抑制纤毛发生。

BACKGROUND: Primary cilia on the surface of eukaryotic cells serve as sensory antennas for the reception and transmission in various cell signaling pathways. They are dynamic organelles that rapidly form during differentiation and cell cycle exit. Defects in these organelles cause a group of wide-ranging disorders called ciliopathies. Tonicity-responsive enhancer-binding protein (TonEBP) is a pleiotropic stress protein that mediates various physiological and pathological cellular responses. TonEBP is well-known for its role in adaptation to a hypertonic environment, to which primary cilia have been reported to contribute. Furthermore, TonEBP is involved in a wide variety of other signaling pathways, such as Sonic Hedgehog and WNT signaling, that promote primary ciliogenesis, suggesting a possible regulatory role. However, the functional relationship between TonEBP and primary ciliary formation remains unclear. METHODS: TonEBP siRNAs and TonEBP-mCherry plasmids were used to examine their effects on cell ciliation rates, assembly and disassembly processes, and regulators. Serum starvation was used as a condition to induce ciliogenesis. RESULTS: We identified a novel pericentriolar localization for TonEBP. The results showed that TonEBP depletion facilitates the formation of primary cilia, whereas its overexpression results in fewer ciliated cells. Moreover, TonEBP controlled the expression and activity of aurora kinase A, a major negative regulator of ciliogenesis. Additionally, TonEBP overexpression inhibited the loss of CP110 from the mother centrioles during the early stages of primary cilia assembly. Finally, TonEBP regulated the localization of PCM1 and AZI1, which are necessary for primary cilia formation. CONCLUSIONS: This study proposes a novel role for TonEBP as a pericentriolar protein that regulates the integrity of centriolar satellite components. This regulation has shown to have a negative effect on ciliogenesis. Investigations into cilium assembly and disassembly processes suggest that TonEBP acts upstream of the aurora kinase A - histone deacetylase 6 signaling pathway and affects basal body formation to control ciliogenesis. Taken together, our data proposes previously uncharacterized regulation of primary cilia assembly by TonEBP.

背景：真核细胞表面的初级纤毛作为各种细胞信号通路中接收和传递的感觉天线。它们是在分化和细胞周期退出过程中快速形成的动态细胞器。这些细胞器的缺陷导致了一组称为纤毛病的广泛疾病。张力反应增强子结合蛋白（TonEBP）是一种多功能应激蛋白，介导各种生理和病理细胞反应。TonEBP 以其适应高渗环境的作用而闻名，初级纤毛据报道有助于适应高渗环境。此外，TonEBP 还参与广泛的其他信号通路，如 Sonic Hedgehog 和 WNT 信号通路，这些通路促进初级纤毛发生，表明可能存在调节作用。然而，TonEBP 与初级纤毛形成之间的功能关系尚不清楚。

方法：使用 TonEBP siRNA 和 TonEBP-mCherry 质粒来研究它们对细胞纤毛率、组装和拆卸过程以及调节剂的影响。血清饥饿被用作诱导纤毛发生的条件。

结果：我们确定了 TonEBP 的一种新的中心体周围定位。结果表明，TonEBP 耗竭促进初级纤毛的形成，而其过表达导致更少的纤毛细胞。此外，TonEBP 控制着 Aurora 激酶 A 的表达和活性，Aurora 激酶 A 是纤毛发生的主要负调控因子。此外，TonEBP 过表达抑制了 CP110 在初级纤毛组装早期从母中心粒丢失。最后，TonEBP 调节 PCM1 和 AZI1 的定位，这对于初级纤毛形成是必要的。

结论：本研究提出了 TonEBP 作为一种中心体周围蛋白的新作用，该蛋白调节中心粒卫星成分的完整性。这种调节对纤毛发生有负面影响。对纤毛组装和拆卸过程的研究表明，TonEBP 作用于 Aurora 激酶 A-组蛋白去乙酰化酶 6 信号通路的上游，并影响基底体形成以控制纤毛发生。总之，我们的数据提出了 TonEBP 对初级纤毛组装的以前未表征的调节作用。