PDF(Pubmed)
Abstract：
Carbohydrate metabolism disorders (CMDs), such as diabetes, galactosemia, and mannosidosis, cause ciliopathy-like multiorgan defects. However, the mechanistic link of cilia to CMD complications is still poorly understood. Herein, we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols. Moreover, environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups. Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane, which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly. In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella. These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.
摘要：
碳水化合物代谢紊乱（CMD），比如糖尿病，半乳糖血症,和甘露多菌病，导致纤毛病样多器官缺陷。然而,纤毛与CMD并发症的机制联系仍然知之甚少.在这里，我们描述了用病理相关的醛糖而不是相应的糖醇治疗细胞时显著的纤毛分解。此外，环境醛能够通过其甲酰基的空间位阻效应触发纤毛分解。机制研究表明，醛刺激细胞外钙通过质膜流入，随后激活钙调蛋白-AuroraA-组蛋白脱乙酰酶6途径以使轴突微管脱乙酰并触发纤毛分解。体内实验进一步表明，Hdac6敲除小鼠对醛诱导的气管纤毛和精子鞭毛的分解具有抗性。这些发现揭示了甲酰基介导的纤毛分解在CMD并发症中的作用。
