COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein

En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science,...

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Autores principales: Liang E, Li X, Fu W, Zhao C, Yang B, Yang Z
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Publicado: Dove Medical Press 2021
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spelling oai:doaj.org-article:08c2487132fd4b6da7e0cc5111993e622021-12-02T17:32:12ZCOP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein1178-2021https://doaj.org/article/08c2487132fd4b6da7e0cc5111993e622021-04-01T00:00:00Zhttps://www.dovepress.com/cop9-signalosome-subunit-3-restricts-neuroinflammatory-responses-durin-peer-reviewed-fulltext-article-NDThttps://doaj.org/toc/1178-2021En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Baoying YangDepartment of Neurosurgery, Guangdong Sanjiu Brain Hospital, No. 578 Shatai Nan Road, Baiyun District, Guangzhou, 510510, People’s Republic of ChinaEmail yby7899@163.comZhonghua YangCentre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, No. 232 Waihuan Dong Road, Panyun District, Guangzhou, 510006, People’s Republic of ChinaEmail yangzhonghua@gzucm.edu.cnBackground: The suppressor of cytokine signaling 3 (SOCS3) is a specific negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling, which is predominantly activated to induce neuroinflammatory response in microglia and functions essential roles during cerebral ischemia-reperfusion (I/R) injury. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a signaling platform controlling protein stability by remodeling of cullin-RING ubiquitin ligases, which is recently reported to specifically recognize proteins with SOCS-box domains. However, whether SOCS3 is related to COP9 signalosome in neuroinflammation during cerebral I/R injury is completely unclear.Methods: Mice subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion, and BV2 microglia cells treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used to mimic cerebral I/R injury. Western blot, qRTPCR, immunofluorescence, and co-Immunoprecipitation assays were performed to explore the regulatory mechanism of SOCS3 on neuroinflammation and the relationship of SOCS3 and COP9 signalosome during cerebral I/R injury.Results: SOCS3 expression is significantly upregulated in microglia during OGD/R treatment, and overexpression of SOCS3 suppresses OGD/R-induced STAT3 activation and inflammatory factor expression. Furthermore, we find that COP9 signalosome subunit 3 (CSN3) interacts with SOCS3 protein to enhance its stability, thereby resulting in restricting OGD/R-induced STAT3 activation and inflammatory response. Moreover, we find that knockdown of CSN3 evidently accelerates STAT3 activation, and aggravates cerebral I/R injury in vivo.Conclusion: CSN3 restricts neuroinflammatory responses during cerebral I/R injury through stabilizing SOCS3 protein and indicates that CSN3 a potential therapeutic target for cerebral I/R injury.Keywords: cerebral ischemia-reperfusion injury, neuroinflammation, suppressor of cytokine signaling 3, constitutive photomorphogenesis 9 signalosome, signal transducer and activator of transcription 3Liang ELi XFu WZhao CYang BYang ZDove Medical Pressarticlecerebral ischemia-reperfusion injuryneuroinflammationsuppressor of cytokine signaling 3constitutive photomorphogenesis 9 signalosomesignal transducer and activator of transcription 3Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol Volume 17, Pp 1217-1227 (2021)
institution DOAJ
collection DOAJ
language EN
topic cerebral ischemia-reperfusion injury
neuroinflammation
suppressor of cytokine signaling 3
constitutive photomorphogenesis 9 signalosome
signal transducer and activator of transcription 3
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
spellingShingle cerebral ischemia-reperfusion injury
neuroinflammation
suppressor of cytokine signaling 3
constitutive photomorphogenesis 9 signalosome
signal transducer and activator of transcription 3
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
Liang E
Li X
Fu W
Zhao C
Yang B
Yang Z
COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
description En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Baoying YangDepartment of Neurosurgery, Guangdong Sanjiu Brain Hospital, No. 578 Shatai Nan Road, Baiyun District, Guangzhou, 510510, People’s Republic of ChinaEmail yby7899@163.comZhonghua YangCentre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, No. 232 Waihuan Dong Road, Panyun District, Guangzhou, 510006, People’s Republic of ChinaEmail yangzhonghua@gzucm.edu.cnBackground: The suppressor of cytokine signaling 3 (SOCS3) is a specific negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling, which is predominantly activated to induce neuroinflammatory response in microglia and functions essential roles during cerebral ischemia-reperfusion (I/R) injury. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a signaling platform controlling protein stability by remodeling of cullin-RING ubiquitin ligases, which is recently reported to specifically recognize proteins with SOCS-box domains. However, whether SOCS3 is related to COP9 signalosome in neuroinflammation during cerebral I/R injury is completely unclear.Methods: Mice subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion, and BV2 microglia cells treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used to mimic cerebral I/R injury. Western blot, qRTPCR, immunofluorescence, and co-Immunoprecipitation assays were performed to explore the regulatory mechanism of SOCS3 on neuroinflammation and the relationship of SOCS3 and COP9 signalosome during cerebral I/R injury.Results: SOCS3 expression is significantly upregulated in microglia during OGD/R treatment, and overexpression of SOCS3 suppresses OGD/R-induced STAT3 activation and inflammatory factor expression. Furthermore, we find that COP9 signalosome subunit 3 (CSN3) interacts with SOCS3 protein to enhance its stability, thereby resulting in restricting OGD/R-induced STAT3 activation and inflammatory response. Moreover, we find that knockdown of CSN3 evidently accelerates STAT3 activation, and aggravates cerebral I/R injury in vivo.Conclusion: CSN3 restricts neuroinflammatory responses during cerebral I/R injury through stabilizing SOCS3 protein and indicates that CSN3 a potential therapeutic target for cerebral I/R injury.Keywords: cerebral ischemia-reperfusion injury, neuroinflammation, suppressor of cytokine signaling 3, constitutive photomorphogenesis 9 signalosome, signal transducer and activator of transcription 3
format article
author Liang E
Li X
Fu W
Zhao C
Yang B
Yang Z
author_facet Liang E
Li X
Fu W
Zhao C
Yang B
Yang Z
author_sort Liang E
title COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
title_short COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
title_full COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
title_fullStr COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
title_full_unstemmed COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein
title_sort cop9 signalosome subunit 3 restricts neuroinflammatory responses during cerebral ischemia/reperfusion injury through stabilizing suppressor of cytokine signaling 3 protein
publisher Dove Medical Press
publishDate 2021
url https://doaj.org/article/08c2487132fd4b6da7e0cc5111993e62
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AT fuw cop9signalosomesubunit3restrictsneuroinflammatoryresponsesduringcerebralischemiareperfusioninjurythroughstabilizingsuppressorofcytokinesignaling3protein
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