COP9 Signalosome Subunit 3 Restricts Neuroinflammatory Responses During Cerebral Ischemia/Reperfusion Injury Through Stabilizing Suppressor of Cytokine Signaling 3 Protein.
cerebral ischemia-reperfusion injury
constitutive photomorphogenesis 9 signalosome
neuroinflammation
signal transducer and activator of transcription 3
suppressor of cytokine signaling 3
Journal
Neuropsychiatric disease and treatment
ISSN: 1176-6328
Titre abrégé: Neuropsychiatr Dis Treat
Pays: New Zealand
ID NLM: 101240304
Informations de publication
Date de publication:
2021
2021
Historique:
received:
30
12
2020
accepted:
22
03
2021
entrez:
29
4
2021
pubmed:
30
4
2021
medline:
30
4
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 33911869
doi: 10.2147/NDT.S298966
pii: 298966
pmc: PMC8075360
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1217-1227Informations de copyright
© 2021 Liang et al.
Déclaration de conflit d'intérêts
The authors reported no conflicts of interest for this work.
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