Research Paper Volume 13, Issue 3 pp 4452—4467
Modeling paraquat-induced lung fibrosis in C. elegans reveals KRIT1 as a key regulator of collagen gene transcription
- 1 Department of Emergency, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, China
- 2 Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China
Received: August 26, 2020 Accepted: November 18, 2020 Published: January 20, 2021https://doi.org/10.18632/aging.202406
How to Cite
Copyright: © 2021 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Paraquat poisoning causes lung fibrosis, which often results in long-term pulmonary dysfunction. Lung fibrosis has been attributed to collagens accumulation, but the underlying regulatory pathway remains unclear. Here we use the genetically tractable C. elegans as a model to study collagen gene transcription in response to paraquat. We find that paraquat robustly up-regulates collagen gene transcription, which is dependent on KRI-1, a poorly studied protein homologous to human KRIT1/CCM1. KRI-1 knockdown prevents paraquat from activating the oxidative stress response transcription factor SKN-1/Nrf2, resulting in reduced collagen transcription and increased paraquat sensitivity. Using human lung fibroblasts (MRC-5), we confirm that both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat. Nrf2 hyper-activation by KEAP1 knockdown bypasses KRIT1 to up-regulate collagen transcription. Our findings on the regulation of collagen gene transcription by paraquat could suggest potential strategies to treat pulmonary fibrosis caused by paraquat poisoning.