Belangrijkste concepten
Upregulation of the ubiquitin ligase TRIM21 promotes the nuclear translocation of PKM2, which in turn activates the STAT3 and NF-κB pathways and enhances glycolysis and proliferation in astrocytes, contributing to the development of experimental autoimmune encephalomyelitis.
Samenvatting
The study investigates the role of PKM2 nuclear translocation in astrocyte activation and the underlying regulatory mechanism in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
Key highlights:
- PKM2 displayed nuclear translocation in astrocytes of EAE mice, which was associated with increased glycolysis and proliferation of astrocytes.
- The ubiquitin ligase TRIM21 was identified to interact with and promote the K63-linked ubiquitination of PKM2, thereby facilitating its nuclear translocation.
- Overexpression of TRIM21 enhanced the nuclear localization of PKM2 and its interaction with transcription factors STAT3 and NF-κB, leading to increased glycolysis and proliferation of astrocytes.
- Knockdown of TRIM21 in astrocytes or inhibition of PKM2 nuclear translocation using TEPP-46 alleviated disease severity, inflammation, and demyelination in the EAE model.
The study provides novel insights into the regulatory mechanism of astrocyte activation mediated by the TRIM21-PKM2 axis, suggesting this pathway as a potential therapeutic target for the treatment of multiple sclerosis and other astrocyte-involved neurological diseases.
Statistieken
Glucose consumption was significantly reduced in MOGsup-stimulated astrocytes treated with DASA-58 compared to untreated controls.
Lactate production was significantly decreased in MOGsup-stimulated astrocytes treated with DASA-58 compared to untreated controls.
Overexpression of TRIM21 increased lactate production and glucose consumption in astrocytes, which was reversed by DASA-58 treatment.
Citaten
"Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines."
"TRIM21 overexpressing in primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58."
"Intracerebroventricular injection of a lentiviral vector to knockdown TRIM21 in astrocytes or intraperitoneal injection of TEPP-46, which inhibit the nuclear translocation of PKM2, effectively decreased disease severity, CNS inflammation and demyelination in EAE."