Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.
PLoS Genet. 2018 Mar 30;14(3):e1007316. doi: 10.1371/journal.pgen.1007316. eCollection 2018 Mar.
Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using Zmynd10-/-mice exhibiting typical PCD phenotypes, including hydrocephalus and laterality defects. In these mutants, morphology, the number of motile cilia, and the 9+2 axoneme structure were normal; however, inner and outer dynein arms (IDA and ODA, respectively) were absent. ZMYND10 interacted with ODA components and proteins, including LRRC6, DYX1C1, and C21ORF59, implicated in the cytoplasmic pre-assembly of DAs, whose levels were significantly reduced in Zmynd10-/-mice. LRRC6 and DNAI1 were more stable when co-expressed with ZYMND10 than when expressed alone. DNAI2, which did not interact with ZMYND10, was not stabilized by co-expression with ZMYND10 alone, but was stabilized by co-expression with DNAI1 and ZMYND10, suggesting that ZMYND10 stabilized DNAI1, which subsequently stabilized DNAI2. Together, these results demonstrated that ZMYND10 regulated the early stage of DA cytoplasmic pre-assembly by stabilizing DNAI1.
锌指 MYND 型结构域蛋白 10（ZMYND10）是一种在纤毛细胞中表达的细胞质蛋白，当其发生突变时会导致原发性纤毛运动障碍（PCD）；然而，其功能尚未完全阐明。因此，在这项研究中，我们使用表现出典型 PCD 表型的 Zmynd10-/-小鼠（包括脑积水和侧性缺陷）来研究 ZMYND10 的作用。在这些突变体中，形态、运动纤毛的数量和 9+2 轴丝结构正常；然而，内、外动力蛋白臂（IDA 和 ODA，分别）缺失。ZMYND10 与 ODA 成分和蛋白相互作用，包括 LRRC6、DYX1C1 和 C21ORF59，这些蛋白参与了 DAs 的细胞质预组装，而 Zmynd10-/-小鼠中这些蛋白的水平显著降低。当与 ZYMND10 共表达时，LRRC6 和 DNAI1 比单独表达时更稳定。虽然不与 ZMYND10 相互作用，但 DNAI2 与 ZMYND10 单独共表达时不会稳定，而与 DNAI1 和 ZMYND10 共表达时会稳定，这表明 ZMYND10 稳定了 DNAI1，随后稳定了 DNAI2。总之，这些结果表明 ZMYND10 通过稳定 DNAI1 来调节 DA 细胞质预组装的早期阶段。
