Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
Elife. 2020 Jun 18;9:e55957. doi: 10.7554/eLife.55957.
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 TurboID 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.
原发性纤毛是发育过程中细胞信号传导和器官稳态所必需的感觉细胞器。纤毛起源于中心体，其形成和功能受许多因素的控制。通过对 Townes-Brocks 综合征（TBS）的研究，这是一种与人类成纤维细胞中纤毛形成异常相关的罕见疾病，我们发现亮氨酸拉链蛋白 LUZP1 是截断 SALL1 的相互作用蛋白，截断 SALL1 是导致该疾病的显性作用蛋白。使用 TurboID 邻近标记和下拉实验，我们表明 LUZP1 与与中心体和肌动蛋白丝相关的因子结合。在这里，我们表明 LUZP1 是一种纤毛调节因子。它定位于中心粒周围和肌动蛋白细胞骨架上。LUZP1 的缺失会降低 F-肌动蛋白水平，促进纤毛发生，并改变 Sonic Hedgehog 信号转导，表明其在细胞骨架-纤毛相互依存关系中起着关键作用。截断的 SALL1 增加了 LUZP1 的泛素蛋白酶体介导的降解。LUZP1 的改变与其他因素一起可能导致 TBS 的发病机制。
