title: Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia-reperfusion injury.
abstract: Cerebral ischemia-reperfusion injury is a major public health concern that causes high rates of disability and mortality in adults. Microglial activation plays a crucial role in ischemic stroke-induced alteration of the immune microenvironment. However, the mechanism underlying the triggering of microglial activation by ischemic stroke remains to be elucidated. Previously, we demonstrated that the protein kinase Hippo/MST1 plays an important role in oxidative stress-induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433, which increases MST1 kinase activity. Microglial activation has been implicated as a secondary detrimental cellular response that contributes to neuronal cell death in ischemic stroke. Here, we are the first, to our knowledge, to demonstrate that MST1 mediates stroke-induced microglial activation by directly phosphorylating IκBα at residues S32 and S36. We further demonstrate that Src kinase functions upstream of MST1-IκB signaling during microglial activation. Specific deletion of MST1 in microglia mitigates stroke-induced brain injury. Therefore, we propose that Src-MST1-IκB signaling plays a critical role in stroke-induced microglial activation. Together with our previous work demonstrating that MST1 is important for oxidative stress-induced neuronal cell death, our results indicate that MST1 could represent a potent therapeutic target for ischemic stroke.
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, Graduate School of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, Graduate School of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Lujun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: The Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, Graduate School of the Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shengyi
authors.initials: S
authors.lastname: Peng
authors.affiliation: Core Facility Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Jia
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
authors.affiliation: The Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Neurology and Radiology, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zqyuan@ibp.ac.cn.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015427:Reperfusion Injury / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D019061:src-Family Kinases / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D019061:src-Family Kinases; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases
keywords: Hippo/MST1; Ischemia; IκB; Microglia; Src