Paraquat is an agonist of STIM1 and increases intracellular calcium levels

Paraquat (PQ) is an efficient herbicide but leads to high mortality with no antidote in mammals. PQ produces reactive oxygen species (ROS), leading to epithelial-mesenchymal transition (EMT) for pulmonary fibrosis in type II alveolar (AT II) cells. Intriguingly, strategies reducing ROS exhibit limit...

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Bibliographic Details
Published in:Communications biology 2022-10, Vol.5 (1), p.1151-11, Article 1151
Main Authors: Yang, Wenyu, Tian, Rui, Zhu, Yong, Huang, Peijie, Ma, Xinrun, Meng, Xiaoxiao, Dai, Wentao, Tao, Yiming, Chen, Daonan, Zhang, Jiaxiang, Lu, Jian, Xie, Hui, Jian, Xiangdong, Yang, Zhengfeng, Wang, Ruilan
Format: Article
Language:English
Subjects:
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Agonists
Alveoli
Animals
Biology
Biomedical and Life Sciences
Calcium
Calcium (extracellular)
Calcium (intracellular)
Calcium influx
Cell death
Epithelial-Mesenchymal Transition
Fibrosis
Herbicides
Intracellular
Life Sciences
Lung diseases
Mammals
Mesenchyme
Paraquat
Paraquat - pharmacology
Pulmonary fibrosis
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - metabolism
Reactive Oxygen Species
STIM1 protein
Toxicity
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Summary:Paraquat (PQ) is an efficient herbicide but leads to high mortality with no antidote in mammals. PQ produces reactive oxygen species (ROS), leading to epithelial-mesenchymal transition (EMT) for pulmonary fibrosis in type II alveolar (AT II) cells. Intriguingly, strategies reducing ROS exhibit limited therapeutic effects, indicating other targets existing for PQ toxicity. Herein we report that PQ is also an agonist for STIM1 that increases intracellular calcium levels. Particularly, PQ promotes STIM1 puncta formation and association with TRPC1 or ORAI for extracellular calcium entry and thus intracellular calcium influx. Further studies reveal the importance of P584&Y586 residues in STIM1 for PQ association that facilitates STIM1 binding to TRPC1. Consequently, the STIM1-TRPC1 route facilitates PQ-induced EMT for pulmonary fibrosis as well as cell death. Our results demonstrate that PQ is an agonist of STIM1 that induces extracellular calcium entry, increases intracellular calcium levels, and thus promotes EMT in AT II cells. The herbicide paraquat is an agonist of Stromal Interaction Molecule 1 (STIM1), leading to extracellular calcium entry observed in epithelial-mesenchymal transition in alveolar cells during pulmonary fibrosis.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-04130-0