Multicilin drives centriole biogenesis via E2f proteins.
Multicilin drives centriole biogenesis via E2f proteins.
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DOI：
10.1101/gad.243832.114
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发表时间：
2014-07-01
影响因子：
10.5
通讯作者：
Kintner C
中科院分区：
文献类型：
--
作者：
Ma L;Quigley I;Omran H;Kintner C
多纤毛细胞（MCCs）在许多器官系统中产生管腔流体流动中起关键作用。为了分化，MCC经历由小卷曲螺旋蛋白multicilin启动的中心粒组装的独特程序。Kintner和他的同事们发现multicilin与e2f4、e2f5和它们的二聚化伴侣dp1形成了一个三元复合物，它激活了中心粒生物发生基因。因此，Multicilin选择细胞周期基因的e2f调控来驱动中心粒组装。此外，这种复合物是禁用的突变，在人类multicilin，导致严重的先天性粘液纤毛清除障碍。多纤毛细胞利用数百个运动纤毛来产生流体流动，它们首先通过组装数百个中心粒来成核和延伸。在大多数细胞中，进入细胞周期允许中心粒进行单轮复制，但在分化的多纤毛细胞中，大量的中心粒组装发生在G0由一个小的卷曲螺旋蛋白Multicilin启动的过程。在这里，我们表明Multicilin通过与E2f4或E2f5和Dp1形成三元复合物来发挥作用，该三元复合物结合并激活中心粒生物发生所需的大多数基因，而其他细胞周期基因保持关闭。该复合物还通过激活deup1的表达而不是其partial cep63的表达来促进中心粒生物发生的后体途径。最后，我们表明，这种复杂的是禁用突变的人Multicilin，导致严重的先天性粘液纤毛清除障碍，由于减少产生的多纤毛。Multicilin通过选择细胞周期基因的E2f调节，以多纤毛细胞分化所需的方式驱动上皮祖细胞中的大量中心粒组装。
Muliciliate cells (MCCs) play critical roles in producing luminal fluid flow in a number of organ systems. To differentiate, MCCs undergo a unique program of centriole assembly initiated by the small coiled-coil protein multicilin. Kintner and colleagues show that multicilin forms a ternary complex with e2f4, e2f5, and their dimerization partner, dp1, which activates centriole biogenesis genes. Multicilin thus coopts the e2f regulation of cell cycle genes to drive centriole assembly. Furthermore, this complex is disabled by mutations in human multicilin that cause a severe congenital mucociliary clearance disorder. Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation.
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影响因子：
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