CircRNA_0001449 disturbs phosphatidylinositol homeostasis and AKT activity by enhancing Osbpl5 translation in transient cerebral ischemia
Fei-Fei Shang,
Li Luo,
Jianghong Yan,
Qiubo Yu,
Yongzheng Guo,
Yuchen Wen,
Xiao-Li Min,
Ling Jiang,
Xiang He,
Wei Liu
Affiliations
Fei-Fei Shang
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
Li Luo
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
Jianghong Yan
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
Qiubo Yu
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
Yongzheng Guo
Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Yuchen Wen
Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
Xiao-Li Min
Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
Ling Jiang
Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province, 550002, China
Xiang He
Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province, 550002, China; Department of Neuroscience, Yale School of Medicine, New Haven, CT, 06510, USA; Corresponding author. Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
Wei Liu
Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Corresponding author.
Phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] is a phosphorylated derivative of phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which recruit and activate AKT in the plasma membrane (PM) to promote cellular survival. ORP5 anchors at the endoplasmic reticulum (ER)-PM contact sites and acts as a PI(4)P and PI(4,5)P2/phosphatidylserine (PS) exchanger. Here, a lipidomics analysis of the sensorimotor cortex revealed that transient middle cerebral artery occlusion (tMCAO) disturbs the homeostasis of phosphatidylinositols (PIs) and PS between the PM and ER. Conditional knockout mice showed that ORP5 contributes to this abnormal distribution. Abolishing the ORP5 gene significantly inhibited apoptosis and autophagy. RNA sequencing and RNA pull down analyses confirmed a competing endogenous RNA pathway in which circ_0001449 sponges miR-124-3p and miR-32-5p to promote Osbpl5 translation. Our data showed that circRNA_0001449 regulates membrane homeostasis via ORP5 and is involved in the AKT survival pathway.
