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

En Liang; Xiaojun Li; Wenjun Fu; Changtong Zhao; Baoying Yang; Zhonghua Yang

doi:10.2147/NDT.S298966

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

Neuropsychiatr Dis Treat. 2021 Apr 22:17:1217-1227. doi: 10.2147/NDT.S298966. eCollection 2021.

Authors

En Liang¹, Xiaojun Li², Wenjun Fu², Changtong Zhao¹, Baoying Yang³, Zhonghua Yang²

Affiliations

¹ Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People's Republic of China.
² Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.
³ Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou, People's Republic of China.

Abstract

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: 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; constitutive photomorphogenesis 9 signalosome; neuroinflammation; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3.

Grants and funding

This study was supported by Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (20201419) and ShenZhen Science and Technology Planning Project (JCYJ20190812163201666).