Faculty of Dentistry, Université de Montréal, Montréal, Québec, Canada.
CHU Sainte-Justine Research Center, Montréal, Québec, Canada.
PLoS One. 2019 Mar 7;14(3):e0213269. doi: 10.1371/journal.pone.0213269. eCollection 2019.
Adolescent Idiopathic Scoliosis (AIS) is a spinal deformity that affects approximately 3 percent of human adolescents. Although the etiology and molecular basis of AIS is unclear, several genes such as POC5 have been identified as possible causes of the condition. In order to understand the role of POC5 in the pathogenesis of AIS, we investigated the subcellular localization of POC5 in cilia of cells over-expressing either the wild type (wt) or an AIS-related POC5 variant POC5A429V. Mutation of POC5 was found to alter its subcellular localization and to induce ciliary retraction. Furthermore, we observed an impaired cell-cycle progression with the accumulation of cells in the S-phase in cells expressing POC5A429V. Using immunoprecipitation coupled to mass spectrometry, we identified specific protein interaction partners of POC5, most of which were components of cilia and cytoskeleton. Several of these interactions were altered upon mutation of POC5. Altogether, our results demonstrate major cellular alterations, disturbances in centrosome protein interactions and cilia retraction in cells expressing an AIS-related POC5 mutation. Our study suggests that defects in centrosomes and cilia may underlie AIS pathogenesis.
青少年特发性脊柱侧凸（AIS）是一种影响约 3%人类青少年的脊柱畸形。尽管 AIS 的病因和分子基础尚不清楚，但已经确定了几个基因，如 POC5，作为该病症的可能原因。为了了解 POC5 在 AIS 发病机制中的作用，我们研究了在过表达野生型（wt）或与 AIS 相关的 POC5 变体 POC5A429V 的细胞的纤毛中 POC5 的亚细胞定位。发现 POC5 的突变改变了其亚细胞定位并诱导纤毛回缩。此外，我们观察到表达 POC5A429V 的细胞中细胞周期进程受损，S 期细胞积累。通过免疫沉淀结合质谱分析，我们鉴定了 POC5 的特定蛋白质相互作用伙伴，其中大多数是纤毛和细胞骨架的组成部分。在 POC5 突变后，其中一些相互作用发生了改变。总之，我们的研究结果表明，在表达与 AIS 相关的 POC5 突变的细胞中，存在主要的细胞改变、中心体蛋白相互作用紊乱和纤毛回缩。我们的研究表明，中心体和纤毛的缺陷可能是 AIS 发病机制的基础。
