BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-11-25 DOI:10.1038/s44319-024-00326-z

Avishek Prasai, Olha Ivashchenko, Kristyna Maskova, Sofiia Bykova, Marketa Schmidt Cernohorska, Ondrej Stepanek, Martina Huranova

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引用次数: 0

Abstract

Bardet-Biedl syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of the BBSome, a cargo adaptor essential for export of transmembrane receptors from cilia. Although actin-dependent ectocytosis has been proposed to compensate defective cargo retrieval, its molecular basis remains unclear, especially in relation to BBS pathology. In this study, we investigated how actin polymerization and ectocytosis are regulated within the cilium. Our findings reveal that ciliary CDC42, a RHO-family GTPase triggers in situ actin polymerization, ciliary ectocytosis, and cilia shortening in BBSome-deficient cells. Activation of the Sonic Hedgehog pathway further enhances CDC42 activity specifically in BBSome-deficient cilia. Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity.

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BBSome 缺陷细胞激活睫状体内 CDC42，触发肌动蛋白依赖性睫状体外吞。

巴尔德-比德尔综合征（Bardet-Biedl Syndrome，BBS）是一种由 BBSome 功能障碍引起的多形性纤毛病，BBSome 是一种货物适配体，对从纤毛中输出跨膜受体至关重要。虽然有人提出肌动蛋白依赖性外吞作用可弥补货物回收的缺陷，但其分子基础仍不清楚，尤其是与 BBS 病理学的关系。在本研究中，我们研究了纤毛内肌动蛋白聚合和外吞是如何调控的。我们的研究结果表明，在BBSome缺陷细胞中，纤毛CDC42（一种RHO家族GTP酶）会引发原位肌动蛋白聚合、纤毛外吞和纤毛缩短。Sonic Hedgehog通路的激活进一步增强了CDC42在BBSome缺陷细胞纤毛中的活性。抑制 BBSome 基因缺陷细胞中的 CDC42 会降低纤毛肌动蛋白聚合事件的频率和持续时间，导致 G 蛋白偶联受体 161 (GPR161) 在 Sonic Hedgehog 信号传导过程中沿轴丝隆起。总之，我们的研究确定了 CDC42 是睫状体外吞的关键触发器。睫状体CDC42和外吞功能亢进以及由此导致的睫状体物质损失可能会导致BBS疾病的严重程度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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