title: ARRB1/β-arrestin-1 mediates neuroprotection through coordination of BECN1-dependent autophagy in cerebral ischemia.
abstract: Autophagy, a highly conserved process conferring cytoprotection against stress, contributes to the progression of cerebral ischemia. β-arrestins are multifunctional proteins that mediate receptor desensitization and serve as important signaling scaffolds involved in numerous physiopathological processes. Here, we show that both ARRB1 (arrestin, β 1) and ARRB2 (arrestin, β 2) were upregulated by cerebral ischemic stress. Knockout of Arrb1, but not Arrb2, aggravated the mortality, brain infarction, and neurological deficit in a mouse model of cerebral ischemia. Accordingly, Arrb1-deficient neurons exhibited enhanced cell injury upon oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Deletion of Arrb1 did not affect the cerebral ischemia-induced inflammation, oxidative stress, and nicotinamide phosphoribosyltransferase upregulation, but markedly suppressed autophagy and induced neuronal apoptosis/necrosis in vivo and in vitro. Additionally, we found that ARRB1 interacted with BECN1/Beclin 1 and PIK3C3/Vps34, 2 major components of the BECN1 autophagic core complex, under the OGD condition but not normal conditions in neurons. Finally, deletion of Arrb1 impaired the interaction between BECN1 and PIK3C3, which is a critical event for autophagosome formation upon ischemic stress, and markedly reduced the kinase activity of PIK3C3. These findings reveal a neuroprotective role for ARRB1, in the context of cerebral ischemia, centered on the regulation of BECN1-dependent autophagosome formation.
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Tian-Ying
authors.initials: TY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wei
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Biochemistry and Cell Biology; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences; Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: Institute of Biochemistry and Cell Biology; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences; Shanghai, China; School of Life Science and Technology; Tongji University; Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
authors.affiliation: Department of Pharmacology; Second Military Medical University; Shanghai, China; Center of Stroke; Beijing Institute for Brain Disorders; Beijing, China.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Miao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D019390:Arrestins / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D051017:Apoptosis Regulatory Proteins; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
keywords: ARRB1; BECN1; autophagy; cerebral ischemia; neuron