Calcium homeostasis is essential for maintaining the viability and function of pancreatic β cells and plays a key role in preventing the development of diabetes. Decreased levels of ATPase sarcoplasmic/endoplasmic reticulum Ca-transporting 2 (ATP2a2), the main calcium pump in β cells, are often found in individuals with diabetes and in diabetic animal models. However, the regulators of ATP2a2 and the molecular mechanisms responsible for controlling ATP2a2 activity remain unclear. Etoposide-induced protein 2.4 () is also down-regulated in β cells of diabetic individuals, whereas the effect of decreased Ei24 level on β-cell function is not clarified. Here, using Cre-LoxP and CRISPR/Cas9-based genomic knockout (KO) approaches to generate pancreatic β cell-specific KO mice and pancreatic β-cell lines, we found that Ei24 regulates ATP2a2 activity. Specifically, we observed that Ei24 binds to ATP2a2 through Ei24 residues 293-299, which we named here the ATP2a2-interacting region (AIR). Loss of Ei24 inactivated ATP2a2, disrupted calcium homeostasis, and deactivated the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-AMP-activated protein kinase (AMPK) pathway. Elevation of calcium concentration in the endoplasmic reticulum or agonist-induced AMPK activation rescued pancreatic β-cell survival and improved glucose tolerance of KO mice. Our findings indicate that targeting the Ei24-ATP2a2 interaction to increase ATP2a2 activity can protect pancreatic β cells and improve glucose homeostasis in diabetic models, suggesting that Ei24 could potentially serve as a target to prevent or manage diabetes.
Tight junction is a structural constitution in cell-cell adhesion and play an important role in the maintenance of permeability and integrity of normal epithelial cell barrier.The protein encoded by Claudin 1 (CLDN1), a member of the claudin family, is an integral membrane protein and a component of tight junction strands. CLDN1 has been proved to regulate the proliferation and metastasis of multiple tumors, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Here, we found that CLDN1 was aberrantly increased in ESCC tissues and cell lines, and mainly distributed in the nucleus of tumor cells. Furthermore, we confirmed that CLDN1 promoted the proliferation and metastasis of ESCC by triggering autophagy both in vitro and in vivo. Mechanically, we validated that CLDN1-induced autophagy via increasing Unc-51 like autophagy activating kinase 1 (ULK1) expression through AMP-activated protein kinase (AMPK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in ESCC cells. Taken together, our findings demonstrated that aberrant expression and distribution of CLDN1 promoted the proliferation and metastasis of esophageal squamous carcinoma by triggering autophagy through AMPK/STAT1/ULK1 signaling pathway. K E Y W O R D S AMPK/STAT1/ULK1 signaling, autophagy, CLDN1, esophageal squamous cell carcinoma, proliferation, and metastasis
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