Endoplasmic reticulum chaperone GRP78 participates in fluoride‐induced autophagy in LS8 cells by regulating the IRE1‐TRAF2‐JNK pathway

Abstract

Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride‐induced cellular stress and autophagy remain unclear. This study investigated ER stress‐induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride‐induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride‐induced ER stress and autophagy, we assessed changes in fluoride‐induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride‐induced autophagy was reduced in GRP78‐silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride‐treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride‐induced damage by inducing ameloblast autophagy.

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“…NAC and 4-PBA pretreatment not only significantly inhibited ERS levels but also significantly inhibited the increase in autophagy. This suggests that ERS may be the upstream mechanism of BDE-209-induced autophagy rather than inhibition, which may be due to the dominant role of the PERK pathway in autophagy regulation . Li et al demonstrated that GRP78 and Beclin-1 proteins play important roles in ERS-induced autophagy .…”

“…This suggests that ERS may be the upstream mechanism of BDE-209-induced autophagy rather than inhibition, which may be due to the dominant role of the PERK pathway in autophagy regulation. 23 Li et al demonstrated that GRP78 and Beclin-1 proteins play important roles in ERS-induced autophagy. 54 Activated ATF6 protein regulates the expression of downstream autophagy-related genes during ERS, leading to the activation of the autophagy pathway, which triggers hepatic steatosis.…”

“…Scientific researchers have proven that adverse factors inducing excessive autophagy could exacerbate tissue damage . PERK and GRP78 are important regulators of autophagy induced by ERS . IRE1 protein is also able to trigger autophagy by regulating the mTOR signaling pathway .…”

“…22 PERK and GRP78 are important regulators of autophagy induced by ERS. 23 IRE1 protein is also able to trigger autophagy by regulating the mTOR signaling pathway. 24 Li et al have shown that exposure to particulate matter initiates autophagy via induction of ERS, resulting in damage to the bronchial epithelium.…”