Basal body proteins regulate Notch signaling through endosomal trafficking
Basal body proteins regulate Notch signaling through endosomal trafficking
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DOI：
10.1242/jcs.130344
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发表时间：
2014-06-01
影响因子：
4
通讯作者：
Zaghloul, Norann A.
中科院分区：
文献类型：
--
作者：
Leitch, Carmen C.;Lodh, Sukanya;Zaghloul, Norann A.
与初级纤毛和基体相关的蛋白质介导许多信号传导途径，但人们对其在 Notch 信号传导中的作用知之甚少。在这里，我们报告说，Bardet-Biedl 综合征蛋白 BBS1 或 BBS4 的缺失会导致斑马鱼报告系和人类细胞系中 Notch 定向转录增加。通路过度激活伴随着Notch受体在质膜和纤毛上的定位减少。在果蝇突变体中，Notch 过度激活可能是由于内体中受体积累所致，最近的研究表明纤毛蛋白参与内体运输，这表明 BBS 突变体中发生过度激活的可能机制。与此一致，我们观察到 BBS1 和 BBS4 与转运所需的内体分选复合物 (ESCRT) 基因 TSG101 以及晚期内体中受体的积累、内体循环减少和溶酶体中受体降解减少的遗传相互作用。我们观察到与 BBS3 中断类似的缺陷。另一种基底体蛋白 ALMS1 的缺失也会增强 Notch 激活和晚期内体中受体的积累，但不会破坏回收。这些发现表明这些蛋白质通过受体的内体运输在Notch 调节中发挥作用。
Proteins associated with primary cilia and basal bodies mediate numerous signaling pathways, but little is known about their role in Notch signaling. Here, we report that loss of the Bardet-Biedl syndrome proteins BBS1 or BBS4 produces increased Notch-directed transcription in a zebrafish reporter line and in human cell lines. Pathway overactivation is accompanied by reduced localization of Notch receptor at both the plasma membrane and the cilium. In Drosophila mutants, overactivation of Notch can result from receptor accumulation in endosomes, and recent studies implicate ciliary proteins in endosomal trafficking, suggesting a possible mechanism by which overactivation occurs in BBS mutants. Consistent with this, we observe genetic interaction of BBS1 and BBS4 with the endosomal sorting complexes required for transport (ESCRT) gene TSG101 and accumulation of receptor in late endosomes, reduced endosomal recycling and reduced receptor degradation in lysosomes. We observe similar defects with disruption of BBS3. Loss of another basal body protein, ALMS1, also enhances Notch activation and the accumulation of receptor in late endosomes, but does not disrupt recycling. These findings suggest a role for these proteins in the regulation of Notch through endosomal trafficking of the receptor.