Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
13 Mar 2024
13 Mar 2024
Historique:
received:
21
08
2023
accepted:
04
03
2024
medline:
15
3
2024
pubmed:
14
3
2024
entrez:
14
3
2024
Statut:
epublish
Résumé
Ubiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface ( https://hochrainerlab.shinyapps.io/StrokeUbiOmics/ ). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.
Identifiants
pubmed: 38480905
doi: 10.1038/s42003-024-06009-8
pii: 10.1038/s42003-024-06009-8
pmc: PMC10937959
doi:
Substances chimiques
Disks Large Homolog 4 Protein
0
Calcium-Calmodulin-Dependent Protein Kinase Type 2
EC 2.7.11.17
Focal Adhesion Kinase 2
EC 2.7.10.2
Phosphotransferases
EC 2.7.-
Ubiquitin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
321Subventions
Organisme : NINDS NIH HHS
ID : R01 NS034179
Pays : United States
Organisme : NINDS NIH HHS
ID : R37 NS034179
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109588
Pays : United States
Organisme : NIH HHS
ID : S10 OD017992
Pays : United States
Informations de copyright
© 2024. The Author(s).
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