Ndel1 suppresses ciliogenesis in proliferating cells by regulating the trichoplein-Aurora A pathway.
Ndel1 suppresses ciliogenesis in proliferating cells by regulating the trichoplein-Aurora A pathway.
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DOI：
10.1083/jcb.201507046
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发表时间：
2016-02-15
期刊：
影响因子：
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通讯作者：
Inagaki M
中科院分区：
文献类型：
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作者：
Inaba H;Goto H;Kasahara K;Kumamoto K;Yonemura S;Inoko A;Yamano S;Wanibuchi H;He D;Goshima N;Kiyono T;Hirotsune S;Inagaki M
Ndel 1是一种位于中心粒近远侧附属物的蛋白质，其功能是抑制增殖细胞中纤毛发生的抑制蛋白-Aurora A通路的上游调节因子。初级纤毛从静止细胞表面伸出，并在细胞周期重新进入时解体。我们以前表明，纤毛重组抑制生长细胞中的Ekaplein介导的极光A激活途径。在这里，我们报告说，Ndel 1，一个众所周知的动力蛋白活性的调制器，定位在subdistal附属物的母亲中心粒，其中成核的初级纤毛。在血清的存在下，Ndel 1耗竭减少了在母亲中心粒处的肌球蛋白，并诱导非预定的初级纤毛形成，其通过强迫肌球蛋白表达或KCTD 17（肌球蛋白的E3连接酶组分蛋白）的共敲低而恢复。血清饥饿诱导短暂的Ndel 1降解，随后在母亲的中心粒中消失。Ndel 1的强制表达抑制了纤毛发生过程中的speakplein降解和轴丝微管延伸，类似于speakplein诱导或KCTD 17敲低。最重要的是，纤毛和静止细胞的比例增加，在新生Ndel 1-hypomorphic小鼠肾小管上皮细胞。因此，Ndel 1作为一种新的上游调节器的抑制初级纤毛组装的speakplein-Aurora A途径。
Ndel1, a protein located at the subdistal appendage of mother centriole, functions as an upstream regulator of the trichoplein–Aurora A pathway that suppresses ciliogenesis in proliferating cells. Primary cilia protrude from the surface of quiescent cells and disassemble at cell cycle reentry. We previously showed that ciliary reassembly is suppressed by trichoplein-mediated Aurora A activation pathway in growing cells. Here, we report that Ndel1, a well-known modulator of dynein activity, localizes at the subdistal appendage of the mother centriole, which nucleates a primary cilium. In the presence of serum, Ndel1 depletion reduces trichoplein at the mother centriole and induces unscheduled primary cilia formation, which is reverted by forced trichoplein expression or coknockdown of KCTD17 (an E3 ligase component protein for trichoplein). Serum starvation induced transient Ndel1 degradation, subsequent to the disappearance of trichoplein at the mother centriole. Forced expression of Ndel1 suppressed trichoplein degradation and axonemal microtubule extension during ciliogenesis, similar to trichoplein induction or KCTD17 knockdown. Most importantly, the proportion of ciliated and quiescent cells was increased in the kidney tubular epithelia of newborn Ndel1-hypomorphic mice. Thus, Ndel1 acts as a novel upstream regulator of the trichoplein–Aurora A pathway to inhibit primary cilia assembly.