OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2.
Animals
Mice
Brain Ischemia
/ metabolism
Infarction, Middle Cerebral Artery
/ complications
Inflammation
/ metabolism
Ischemic Stroke
/ metabolism
Microglia
/ metabolism
NF-kappa B
/ metabolism
Reperfusion Injury
/ metabolism
Receptor-Interacting Protein Serine-Threonine Kinase 2
/ metabolism
Ubiquitin-Specific Proteases
/ metabolism
Cerebral ischemic injury
Inflammation
OTUD1
RIP2
Ubiquitination
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
received:
19
06
2023
accepted:
22
11
2023
medline:
29
11
2023
pubmed:
28
11
2023
entrez:
28
11
2023
Statut:
epublish
Résumé
Inflammatory response triggered by innate immunity plays a pivotal element in the progress of ischemic stroke. Receptor-interacting kinase 2 (RIP2) is implicated in maintaining immunity homeostasis and regulating inflammatory response. However, the underlying mechanism of RIP2 in ischemic stroke is still not well understood. Hence, the study investigated the role and the ubiquitination regulatory mechanism of RIP2 in ischemic stroke. Focal cerebral ischemia was introduced by middle cerebral artery occlusion (MCAO) in wild-type (WT) and OTUD1-deficient (OTUD1 Our results showed upregulated protein levels of RIP2 and OTUD1 in microglia and astrocytes in mice subjected to focal cerebral ischemia. Inhibition of RIP2 by GSK559 ameliorated the cerebral ischemic outcome by repressing the NF-κB activity and the inflammatory response. Mechanistically, OTUD1 interacted with RIP2 and sequentially removed the K63-linked polyubiquitin chains of RIP2, thereby inhibiting NF-κB activation. Furthermore, OTUD1 deficiency exacerbated cerebral ischemic injury in response to inflammation induced by RIP2 ubiquitination. These findings suggested that RIP2 mediated cerebral ischemic lesion via stimulating inflammatory response, and OTUD1 ameliorated brain injury after ischemia through inhibiting RIP2-induced NF-κB activation by specifically cleaving K63-linked ubiquitination of RIP2.
Sections du résumé
BACKGROUND
BACKGROUND
Inflammatory response triggered by innate immunity plays a pivotal element in the progress of ischemic stroke. Receptor-interacting kinase 2 (RIP2) is implicated in maintaining immunity homeostasis and regulating inflammatory response. However, the underlying mechanism of RIP2 in ischemic stroke is still not well understood. Hence, the study investigated the role and the ubiquitination regulatory mechanism of RIP2 in ischemic stroke.
METHODS
METHODS
Focal cerebral ischemia was introduced by middle cerebral artery occlusion (MCAO) in wild-type (WT) and OTUD1-deficient (OTUD1
RESULTS
RESULTS
Our results showed upregulated protein levels of RIP2 and OTUD1 in microglia and astrocytes in mice subjected to focal cerebral ischemia. Inhibition of RIP2 by GSK559 ameliorated the cerebral ischemic outcome by repressing the NF-κB activity and the inflammatory response. Mechanistically, OTUD1 interacted with RIP2 and sequentially removed the K63-linked polyubiquitin chains of RIP2, thereby inhibiting NF-κB activation. Furthermore, OTUD1 deficiency exacerbated cerebral ischemic injury in response to inflammation induced by RIP2 ubiquitination.
CONCLUSIONS
CONCLUSIONS
These findings suggested that RIP2 mediated cerebral ischemic lesion via stimulating inflammatory response, and OTUD1 ameliorated brain injury after ischemia through inhibiting RIP2-induced NF-κB activation by specifically cleaving K63-linked ubiquitination of RIP2.
Identifiants
pubmed: 38012669
doi: 10.1186/s12974-023-02968-7
pii: 10.1186/s12974-023-02968-7
pmc: PMC10680203
doi:
Substances chimiques
NF-kappa B
0
Otud1 protein, mouse
EC 3.4.19.12
Ripk2 protein, mouse
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinase 2
EC 2.7.11.1
Ubiquitin-Specific Proteases
EC 3.4.19.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
281Subventions
Organisme : National Natural Science Foundation of China
ID : 81873748
Organisme : National Natural Science Foundation of China
ID : 81971193
Organisme : National Natural Science Foundation of China
ID : 81571171
Organisme : Natural Science Foundation of Shandong Province
ID : ZR2023MH254
Informations de copyright
© 2023. The Author(s).
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