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Upregulation of Ubiquitin Ligase TRIM21 Promotes Nuclear Translocation of PKM2 and Astrocyte Activation in Experimental Autoimmune Encephalomyelitis


Core Concepts
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.
Abstract
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.
Stats
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.
Quotes
"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."

Deeper Inquiries

How might the TRIM21-PKM2 axis be regulated by upstream signaling pathways or environmental cues in the context of astrocyte activation and neurological disease progression?

In the context of astrocyte activation and neurological disease progression, the TRIM21-PKM2 axis could be regulated by various upstream signaling pathways and environmental cues. One potential regulatory mechanism could involve inflammatory cytokines, such as TNF-α and IL-6, which are known to be elevated in neurological diseases like multiple sclerosis. These cytokines can activate signaling pathways like NF-κB and STAT3, which are also targets of PKM2 nuclear activity. The interaction between TRIM21 and PKM2 may be enhanced in response to inflammatory signals, leading to increased nuclear translocation of PKM2 and subsequent activation of NF-κB and STAT3 pathways. Additionally, growth factors and neurotransmitters present in the CNS microenvironment could also influence the TRIM21-PKM2 axis. For example, growth factors like EGF or PDGF may stimulate PKM2 nuclear translocation through activation of receptor tyrosine kinases and downstream signaling cascades. Neurotransmitters such as glutamate or dopamine could modulate PKM2 activity and localization through G protein-coupled receptors and intracellular signaling pathways. Furthermore, oxidative stress and mitochondrial dysfunction, common features of neurological disorders, may impact the TRIM21-PKM2 axis. Reactive oxygen species (ROS) generated under oxidative stress conditions could activate TRIM21 and promote its interaction with PKM2, leading to increased nuclear translocation. Mitochondrial dysfunction could alter cellular metabolism and signaling pathways, indirectly affecting the regulation of PKM2 by TRIM21.

How might the TRIM21-PKM2 axis be regulated by upstream signaling pathways or environmental cues in the context of astrocyte activation and neurological disease progression?

In addition to glycolysis and proliferation, the nuclear translocation of PKM2 in astrocytes and other CNS cell types could influence various cellular processes and functions. One important aspect is the regulation of gene expression and transcription. Nuclear PKM2 has been shown to act as a transcriptional coactivator, interacting with transcription factors like c-myc and regulating the expression of genes involved in cell growth, survival, and metabolism. Therefore, the nuclear translocation of PKM2 could impact the transcriptional landscape of astrocytes and other CNS cells, influencing their functional phenotype. Moreover, the nuclear activity of PKM2 may also affect DNA repair mechanisms and genomic stability. PKM2 has been implicated in DNA damage response pathways and the maintenance of genome integrity. Its nuclear function in repairing DNA lesions and preventing mutations could be crucial for the overall health and function of CNS cells, especially under conditions of neurodegenerative diseases or brain injuries where DNA damage is prevalent. Furthermore, the interaction of nuclear PKM2 with signaling pathways like NF-κB and STAT3 could have broader implications for immune responses and inflammation in the CNS. Activation of these pathways by nuclear PKM2 may modulate the inflammatory environment in neurological disorders, impacting disease progression and tissue damage. Additionally, the crosstalk between PKM2 and other signaling molecules in the nucleus could regulate cell fate decisions, differentiation, and synaptic plasticity in the CNS.

Could targeting the TRIM21-PKM2 axis have broader therapeutic implications for neurological disorders beyond multiple sclerosis, such as neurodegenerative diseases or brain injuries?

Targeting the TRIM21-PKM2 axis could indeed have broader therapeutic implications for a range of neurological disorders beyond multiple sclerosis. In neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's, dysregulation of astrocyte function and metabolism is a common feature. The TRIM21-PKM2 axis, with its role in regulating astrocyte activation and glycolysis, could be a potential target for modulating disease progression in these conditions. By inhibiting the nuclear translocation of PKM2 through TRIM21, it may be possible to mitigate the metabolic changes and inflammatory responses associated with neurodegenerative diseases. In the context of brain injuries, such as traumatic brain injury (TBI) or stroke, the TRIM21-PKM2 axis could also play a significant role in the pathophysiology and recovery process. Astrocyte activation and metabolic reprogramming are key events in the response to brain injuries, and targeting PKM2 nuclear translocation via TRIM21 could potentially modulate these processes. By reducing inflammation, promoting tissue repair, and enhancing neuroprotection, interventions targeting the TRIM21-PKM2 axis may offer therapeutic benefits in improving outcomes and reducing long-term neurological deficits following brain injuries. Overall, the TRIM21-PKM2 axis represents a novel and promising target for therapeutic intervention in a variety of neurological disorders, offering the potential to modulate astrocyte function, metabolic reprogramming, and inflammatory responses in the CNS. Further research and preclinical studies are warranted to explore the full therapeutic potential of targeting this axis in diverse neurological conditions.
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