KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability.
KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability.
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DOI：
10.1083/jcb.201607032
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Mill P
中科院分区：
文献类型：
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作者：
Yeyati PL;Schiller R;Mali G;Kasioulis I;Kawamura A;Adams IR;Playfoot C;Gilbert N;van Heyningen V;Wills J;von Kriegsheim A;Finch A;Sakai J;Schofield CJ;Jackson IJ;Mill P
Yeyati等人证明，组蛋白去甲基化酶KDM 3A通过转录和直接结合肌动蛋白调节肌动蛋白动力学，作为纤毛发生的负调节因子。KDM 3A影响当地的肌动蛋白网络，以限制鞭毛内运输在纤毛发生;在它的情况下，纤毛变得不稳定与异常的长度和积累的鞭毛内运输蛋白。纤毛组装和拆卸耦合到肌动蛋白动力学，确保在环境变化的连贯细胞反应。如何将这些进程结合起来仍然没有明确的定义。组蛋白赖氨酸脱甲基酶KDM 3A在生物体内平衡中起重要作用。Kdm 3a表型特征的功能丧失小鼠模型与人类纤毛病变相关，而人类体细胞突变与癌症预后不良相关。我们表明，KDM 3A的情况下有利于纤毛发生，但这些产生的纤毛有一个异常宽的轴丝长度，延迟拆卸和积累鞭毛内运输（IFT）蛋白。KDM 3A通过调节肌动蛋白基因表达和与肌动蛋白细胞骨架结合而发挥双重作用，产生涉及ARP 2/3活性和IFT的响应性“肌动蛋白门”。促进肌动蛋白丝形成拯救KDM 3A突变体纤毛缺陷相反，同时解聚肌动蛋白网络和IFT过表达模仿异常纤毛性状的KDM 3A突变体。因此，KDM 3A是纤毛发生的负调节因子，其通过调节肌动蛋白动力学来控制IFT蛋白向纤毛中的募集。
Yeyati et al. demonstrate that the histone demethylase KDM3A acts as a negative regulator of ciliogenesis by modulating actin dynamics, both transcriptionally and by directly binding actin. KDM3A influences local actin networks to restrict intraflagellar transport during ciliogenesis; in its absence, cilia become unstable with abnormal lengths and accumulated intraflagellar transport proteins. Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models of Kdm3a phenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive “actin gate” that involves ARP2/3 activity and IFT. Promoting actin filament formation rescues KDM3A mutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits of KDM3A mutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.