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CEP290 对于纤毛过渡区的起始组装是必需的。

CEP290 is essential for the initiation of ciliary transition zone assembly.

机构信息

Chinese Academy of Sciences Key Laboratory of Insect Developmental and Evolutionary Biology, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.

University of Chinese Academy of Sciences, Beijing, China.

出版信息

PLoS Biol. 2020 Dec 28;18(12):e3001034. doi: 10.1371/journal.pbio.3001034. eCollection 2020 Dec.

DOI:10.1371/journal.pbio.3001034
PMID:33370260
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7793253/
Abstract

Cilia play critical roles during embryonic development and adult homeostasis. Dysfunction of cilia leads to various human genetic diseases, including many caused by defects in transition zones (TZs), the "gates" of cilia. The evolutionarily conserved TZ component centrosomal protein 290 (CEP290) is the most frequently mutated human ciliopathy gene, but its roles in ciliogenesis are not completely understood. Here, we report that CEP290 plays an essential role in the initiation of TZ assembly in Drosophila. Mechanistically, the N-terminus of CEP290 directly recruits DAZ interacting zinc finger protein 1 (DZIP1), which then recruits Chibby (CBY) and Rab8 to promote early ciliary membrane formation. Complete deletion of CEP290 blocks ciliogenesis at the initiation stage of TZ assembly, which can be mimicked by DZIP1 deletion mutants. Remarkably, expression of the N-terminus of CEP290 alone restores the TZ localization of DZIP1 and subsequently ameliorates the defects in TZ assembly initiation in cep290 mutants. Our results link CEP290 to DZIP1-CBY/Rab8 module and uncover a previously uncharacterized important function of CEP290 in the coordination of early ciliary membrane formation and TZ assembly.

摘要

纤毛在胚胎发育和成人稳态中起着关键作用。纤毛功能障碍会导致各种人类遗传疾病，包括许多由纤毛过渡区（TZ）缺陷引起的疾病。进化上保守的 TZ 成分中心体蛋白 290（CEP290）是最常突变的人类纤毛病基因，但它在纤毛发生中的作用尚未完全阐明。在这里，我们报告 CEP290 在果蝇中 TZ 组装的起始中发挥重要作用。在机制上，CEP290 的 N 端直接招募 DAZ 相互作用锌指蛋白 1（DZIP1），然后招募 Chibby（CBY）和 Rab8 以促进早期纤毛膜的形成。CEP290 的完全缺失会在 TZ 组装的起始阶段阻断纤毛发生，这可以通过 DZIP1 缺失突变体来模拟。值得注意的是，CEP290 的 N 端的单独表达可恢复 DZIP1 的 TZ 定位，并随后改善 cep290 突变体中 TZ 组装起始的缺陷。我们的研究结果将 CEP290 与 DZIP1-CBY/Rab8 模块联系起来，并揭示了 CEP290 在协调早期纤毛膜形成和 TZ 组装中的一个以前未被描述的重要功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b199d3ea5288/pbio.3001034.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/01d3ccb7abe0/pbio.3001034.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b3d35f1f49aa/pbio.3001034.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/43b884e44344/pbio.3001034.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/2ae8f9d59bb5/pbio.3001034.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/300bdcb9650f/pbio.3001034.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b3bd8519ef43/pbio.3001034.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b199d3ea5288/pbio.3001034.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/01d3ccb7abe0/pbio.3001034.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b3d35f1f49aa/pbio.3001034.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/43b884e44344/pbio.3001034.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/2ae8f9d59bb5/pbio.3001034.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/300bdcb9650f/pbio.3001034.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b3bd8519ef43/pbio.3001034.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0ce/7793253/b199d3ea5288/pbio.3001034.g007.jpg

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