Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial–mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis.

This article has an associated First Person interview with the first authors of the paper.

矽肺的特征是二氧化硅暴露引起的肺间质纤维化和矽肺结节的形成，导致肺硬化。由 α-微管蛋白 N-乙酰转移酶 1 (α-TAT1) 介导的微管乙酰化是一种翻译后修饰，可促进微管对机械刺激的稳定性。矽肺中α-TAT1和下游乙酰化α-微管蛋白（Ac-α-Tub）减少，促进上皮间质转化（EMT）；然而，潜在的机制是未知的。我们发现二氧化硅、基质硬化或它们的组合触发了肺泡上皮细胞中的 Ac-α-Tub 下调，随后是 DNA 损伤和复制应激。α-TAT1 升高 Ac-α-Tub 以通过运输 p53 结合蛋白 1（53BP1，也称为 TP53BP1）来限制复制应激和 EMT。结果提供证据表明，α-TAT1 和 Ac-α-Tub 通过防止 53BP1 错误定位和缓解 DNA 损伤来抑制 EMT 和矽肺纤维化。这项研究深入了解了 EMT 期间细胞周期是如何调节的，以及为什么 α-TAT1 和 Ac-α-Tub 的减少会促进矽肺纤维化。

本文对论文的第一作者进行了相关的第一人称采访。