Handling Editor: Andrew Ewald
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, 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: H.X., Shifeng Li; Methodology: G.L., S.C., Y.Z.; Software: S.C., L.Z.; Validation: G.L., S.C., Y.Z., X.G., W.C.; Formal analysis: D.X., Z.W.; Investigation: G.L., S.C., N.M., Shumin Li; Resources: Shifeng Li; Writing - original draft: G.L., S.C.; Writing - review & editing: H.X., Shifeng Li; Supervision: F.Y., H.L., Shifeng Li; Project administration: Shifeng Li; Funding acquisition: H.X., Z.W., F.Y., Shifeng Li.
Funding
This work was supported by the National Natural Science Foundation of China (82003406, 81972988), the Natural Science Foundation of Hebei Province (H2020209287), the Colleges and Universities in Hebei Province Science and Technology Research Project (ZD2019077), the Science and Technology Plan Project of Tangshan City (20130206b) and the Medical Research Foundation of Hebei Health Commission (20191107).
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.243394.supplemental
- Received January 8, 2020.
- Accepted November 12, 2020.
- © 2021. Published by The Company of Biologists Ltd
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