Paraquat is an agonist of STIM1 and Increases Intracellular Calcium Levels

Abstract Paraquat (PQ) is an efficient herbicide utilized worldwide but leads to pulmonary fibrosis and high mortality with no antidote in mammals. PQ is well recognized to produce amounts of ROS, leading to epithelial-mesenchymal transition (EMT) in type II alveolar (AT II) cells, followed with pulmonary fibrosis. Intriguingly, strategies developed to target oxidative stress exhibit limited therapeutic effects, indicating that other molecular targets exist for PQ toxicity. Herein we reported that PQ is also an agonist for STIM1 that increases intracellular calcium levels. Particularly, PQ promotes STIM1 puncta formation and association with TRPC1 or ORAI1 for store-operated calcium entry (SOCE), which increases intracellular calcium levels and NFAT activation. Further studies revealed the importance of P584&Y586 residues in STIM1 for PQ association that facilitates STIM1 binding to TRPC1 for extracellular calcium entry. Consequently, activation of the STIM1-TRPC1 route facilitates PQ-induced EMT for pulmonary fibrosis. Correspondingly, PQ-poisoned patients exhibit specifically reduced blood calcium levels, which is correlated with the severity of PQ poisoning. Taken together, our results demonstrate that PQ is the agonist of STIM1 that induces extracellular calcium entry, increases intracellular calcium levels and thus promotes EMT in AT II cells, which would provide another important molecular target for treating PQ poisoning.