Phlda3 regulates beta cell survival during stress

作者：Mohammed Bensellam, Jeng Yie Chan, Kailun Lee, Mugdha V. Joglekar, Anandwardhan A. Hardikar, Thomas Loudovaris, Helen E. Thomas, Jean‐Christophe Jonas, D. Ross Laybutt · 发表于：Scientific Reports · 年份：2019 · DOI：10.1038/s41598-019-49289-5 · 被引用次数：33 · 研究领域：Pancreatic function and diabetes、Endoplasmic Reticulum Stress and Disease、Diabetes and associated disorders

Abstract The loss of functional beta cell mass characterises all forms of diabetes. Beta cells are highly susceptible to stress, including cytokine, endoplasmic reticulum (ER) and oxidative stress. This study examined the role of pleckstrin homology-like, domain family A, member 3 ( Phlda3 ) in beta cell survival under stress conditions and the regulatory basis. We found that the mRNA levels of Phlda3 were markedly upregulated in vivo in the islets of diabetic humans and mice. In vitro , exposure of MIN6 cells or islets to cytokines, palmitate, thapsigargin or ribose upregulated Phlda3 mRNA and protein levels, concurrent with the induction of ER stress ( Ddit3 and Trb3 ) and antioxidant ( Hmox1 ) genes. Furthermore, H 2 O 2 treatment markedly increased PHLDA3 immunostaining in human islets. Phlda3 expression was differentially regulated by adaptive ( Xbp1 ) and apoptotic ( Ddit3 ) unfolded protein response (UPR) mediators. siRNA-mediated knockdown of Xbp1 inhibited the induction of Phlda3 by cytokines and palmitate, whereas knockdown of Ddit3 upregulated Phlda3 . Moreover, knockdown of Phlda3 potentiated cytokine-induced apoptosis in association with upregulation of inflammatory genes ( iNos , IL1β and IκBα ) and NFκB phosphorylation and downregulation of antioxidant ( Gpx1 and Srxn1 ) and adaptive UPR ( Xbp1 , Hspa5 and Fkbp11 ) genes. Knockdown of Phlda3 also potentiated apoptosis under oxidative stress conditions induced by ribose treatment. These findings suggest that Phl...