Abstract
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). The results provide evidence that α-TAT1/Ac-α-Tub inhibits 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/Ac-α-Tub promotes silicosis fibrosis.
- Received January 8, 2020.
- Accepted November 12, 2020.
- © 2020. Published by The Company of Biologists Ltd
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