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 a 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.

中文翻译：

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病理相关的醛糖和环境醛通过甲酰基介导的机制导致纤毛解体

碳水化合物代谢紊乱（CMD），例如糖尿病、半乳糖血症和甘露糖苷中毒，会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知之甚少。在此，我们描述了用病理相关的醛糖而不是相应的糖醇处理细胞后显着的纤毛分解。此外，环境醛能够通过其甲酰基的空间位阻效应引发纤毛分解。机制研究表明，醛类刺激细胞外钙跨质膜流入，随后激活钙调素-Aurora A-组蛋白脱乙酰酶 6 途径，使轴丝微管脱乙酰化并引发纤毛解体。体内实验进一步表明，Hdac6 敲除小鼠对乙醛诱导的气管纤毛和精子鞭毛分解具有抵抗力。这些发现揭示了甲酰基介导的纤毛分解在 CMD 并发症中的先前未被认识的作用。