LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome
LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome
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DOI：
10.7554/elife.55957
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发表时间：
2020-06-18
期刊：
影响因子：
7.7
通讯作者：
Barrio, Rosa
中科院分区：
文献类型：
--
作者：
Bozal-Basterra, Laura;Gonzalez-Santamarta, Maria;Barrio, Rosa
初级纤毛是在细胞发育和器官平衡过程中至关重要的感觉细胞器。纤毛起源于中心体，其形成和功能受多种因素的制约。通过对townes - broks综合征（TBS）的研究，我们发现亮氨酸拉链蛋白LUZP1是导致该疾病的显性蛋白截断SALL1的相互作用物。TBS是一种罕见的疾病，与人类成纤维细胞中异常的毛毛形成有关。使用TurbolD接近标记和下拉，我们发现LUZP1与中心体和肌动蛋白丝相关的因子相关。在这里，我们证明了LUZP1是一个纤毛调节器。它定位于中心粒周围和肌动蛋白细胞骨架。LUZP1的缺失降低了f -肌动蛋白水平，促进了纤毛的发生，并改变了Sonic Hedgehog信号，指出了细胞骨架-纤毛相互依赖的关键作用。截断的SALL1增加了泛素蛋白酶体介导的LUZP1降解。与其他因素一起，LUZP1的改变可能有助于TBS病因学。
Primary cilia are sensory organelles crucial for cell signaling during development and organ homeostasis. Cilia arise from centrosomes and their formation and function is governed by numerous factors. Through our studies on Townes-Brocks Syndrome (TBS), a rare disease linked to abnormal cilia formation in human fibroblasts, we uncovered the leucine-zipper protein LUZP1 as an interactor of truncated SALL1, a dominantly-acting protein causing the disease. Using TurbolD proximity labeling and pulldowns, we show that LUZP1 associates with factors linked to centrosome and actin filaments. Here, we show that LUZP1 is a cilia regulator. It localizes around the centrioles and to actin cytoskeleton. Loss of LUZP1 reduces F-actin levels, facilitates ciliogenesis and alters Sonic Hedgehog signaling, pointing to a key role in cytoskeleton-cilia interdependency. Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1. Together with other factors, alterations in LUZP1 may be contributing to TBS etiology.