Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12697-702. doi: 10.1073/pnas.1300968110. Epub 2013 Jul 15.
Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by defective cilia motility. The identified PCD genes account for about half of PCD incidences and the underlying mechanisms remain poorly understood. We demonstrate that Reptin/Ruvbl2, a protein known to be involved in epigenetic and transcriptional regulation, is essential for cilia motility in zebrafish. We further show that Reptin directly interacts with the PCD protein Lrrc6/Seahorse and this interaction is critical for the in vivo function of Lrrc6/Seahorse in zebrafish. Moreover, whereas the expression levels of multiple dynein arm components remain unchanged or become elevated, the density of axonemal dynein arms is reduced in reptin(hi2394) mutants. Furthermore, Reptin is highly enriched in the cytosol and colocalizes with Lrrc6/Seahorse. Combined, these results suggest that the Reptin-Lrrc6/Seahorse complex is involved in dynein arm formation. We also show that although the DNA damage response is induced in reptin(hi2394) mutants, it remains unchanged in cilia biogenesis mutants and lrrc6/seahorse mutants, suggesting that increased DNA damage response is not intrinsic to ciliary defects and that in vertebrate development, Reptin functions in multiple processes, both cilia specific and cilia independent.
原发性纤毛运动障碍（PCD）是一种常染色体隐性遗传病，由纤毛运动缺陷引起。已鉴定的 PCD 基因约占 PCD 发病率的一半，其潜在机制仍知之甚少。我们证明 Reptin/Ruvbl2 是一种已知参与表观遗传和转录调控的蛋白质，对于斑马鱼的纤毛运动是必不可少的。我们进一步表明 Reptin 直接与 PCD 蛋白 Lrrc6/海马体相互作用，这种相互作用对于 Lrrc6/海马体在斑马鱼中的体内功能至关重要。此外，虽然多个动力蛋白臂成分的表达水平保持不变或升高，但 reptin(hi2394)突变体中轴丝动力蛋白臂的密度降低。此外，Reptin 在细胞质中高度富集，并与 Lrrc6/海马体共定位。综上所述，这些结果表明 Reptin-Lrrc6/海马体复合物参与了动力蛋白臂的形成。我们还表明，尽管 reptin(hi2394)突变体中诱导了 DNA 损伤反应，但在纤毛发生突变体和 lrrc6/seahorse 突变体中未发生变化，这表明增加的 DNA 损伤反应不是纤毛缺陷所固有，并且在脊椎动物发育过程中，Reptin 在多个过程中发挥作用，既特异性地也非特异性地作用于纤毛。
