Upregulated expression of ubiquitin ligase TRIM21 promotes PKM2 nuclear translocation and astrocyte activation in experimental autoimmune encephalomyelitis
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ABSTRACT:
PROVIDER: PRJNA1099677 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28644900.fastq.gz | Fastqsanger.gz | |||
| SRR28644901.fastq.gz | Fastqsanger.gz | |||
| SRR28644902.fastq.gz | Fastqsanger.gz | |||
| SRR28644903.fastq.gz | Fastqsanger.gz | |||
| SRR28644904.fastq.gz | Fastqsanger.gz |
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Project description:Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. We found that PKM2 displayed nuclear translocation in astrocytes of EAE mice, an animal model of multiple sclerosis. And we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. To detect the expression of TRM21 in EAE mice, We used single-cell sequencing to analyze the expression of TRM21 in EAE mice.
2024-09-12 | GSE263883 | GEO
Project description:Reactive astrocytes play critical roles in the occurrence of various neurological diseases such as multiple sclerosis. Activation of astrocytes is often accompanied by a glycolysis-dominant metabolic switch. However, the role and molecular mechanism of metabolic reprogramming in activation of astrocytes have not been clarified. Here, we found that PKM2, a rate-limiting enzyme of glycolysis, displayed nuclear translocation in astrocytes of EAE (experimental autoimmune encephalomyelitis) mice, an animal model of multiple sclerosis. Prevention of PKM2 nuclear import by DASA-58 significantly reduced the activation of mice primary astrocytes, which was observed by decreased proliferation, glycolysis and secretion of inflammatory cytokines. Most importantly, we identified the ubiquitination-mediated regulation of PKM2 nuclear import by ubiquitin ligase TRIM21. TRIM21 interacted with PKM2, promoted its nuclear translocation and stimulated its nuclear activity to phosphorylate STAT3, NF-κB and interact with c-myc. Further single-cell RNA sequencing and immunofluorescence staining demonstrated that TRIM21 expression was upregulated in astrocytes of EAE. TRIM21 overexpressing in mice primary astrocytes enhanced PKM2-dependent glycolysis and proliferation, which could be reversed by DASA-58. Moreover, 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. Collectively, our study provides novel insights into the pathological function of nuclear glycolytic enzyme PKM2 and ubiquitination-mediated regulatory mechanism that are involved in astrocyte activation. Targeting this axis may be a potential therapeutic strategy for the treatment of astrocyte-involved neurological disease.
| S-EPMC11392529 | biostudies-literature
Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.
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Project description:Pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, plays a critical role in macrophage activation and a broad spectrum of chronic liver diseases. However, whether PKM2 contributes to the pathogenesis of acute liver injury (ALI) remains largely unexplored. By bioinformatic screening and analysis of ALI liver, we found that PKM2 was significantly upregulated in the liver tissues of ALI patients and mice. Immunofluorescence staining further demonstrated that PKM2 was markedly upregulated in macrophages during ALI progression. Notably, macrophage PKM2 depletion effectively alleviated acetaminophen (APAP)- and lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALI, as demonstrated by ameliorated immune cells infiltration, pro-inflammatory mediators, and hepatocellular cell death. PKM2-deficient macrophages showed M2 anti-inflammatory polarization in vivo and in vitro. Furthermore, PKM2 deletion limited HIF-1α signaling and aerobic glycolysis of macrophages, which thereby attenuated macrophage pro-inflammatory activation and hepatocyte injury. Pharmacological PKM2 antagonist efficiently ameliorated liver injury and prolonged the survival of mice in APAP-induced ALI model. Our study highlights the pivotal role of macrophage PKM2 in advancing ALI, and therapeutic targeting of PKM2 may serve as a novel strategy to combat ALI.
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Project description:The tripartite motif (TRIM) protein family is an E3 ubiquitin ligase family. Recent reports have indicated that some TRIM proteins have antiviral functions, especially against retroviruses. However, most studies mainly focus on the relationship between TRIM21 and interferon or other antiviral effectors. The effect of TRIM21 on virus-encoded proteins remains unclear. In this study, we screened candidate interacting proteins of HBV DNA polymerase (Pol) by FLAG affinity purification and mass spectrometry assay and identified TRIM21 as its regulator. We used a coimmunoprecipitation (co-IP) assay to demonstrate that TRIM21 interacted with the TP domain of HBV DNA Pol. In addition, TRIM21 promoted the ubiquitination and degradation of HBV DNA Pol using its RING domain, which has E3 ubiquitin ligase activity. Lys260 and Lys283 of HBV DNA Pol were identified as targets for ubiquitination mediated by TRIM21. Finally, we uncovered that TRIM21 degrades HBV DNA Pol to restrict HBV DNA replication, and its SPRY domain is critical for this activity. Taken together, our results indicate that TRIM21 suppresses HBV DNA replication mainly by promoting the ubiquitination of HBV DNA Pol, which may provide a new potential target for the treatment of HBV.
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Project description:Purpose: In this study, we compared transcriptome profiling (RNA-seq) between normal mouse embryonic stem cell (E14) and Hexokinase2 (Hk2)/ Pyruvate Kinase M2 (Pkm2) overexpressed E14 cell. Result: Using an optimized data analysis workflow, we mapped over 4 billion sequence reads per sample to the mouse genome (build mm9) and identified 28698 transcripts in 5 samples. Conclusion: Our study represents the first detailed analysis of Hk2/ Pkm2 overexpressed E14 cell transcriptomes, generated by RNA-seq technology We compared transcriptome profiling (RNA-Seq) between normal mouse embryonic stem cell (E14) and E14 cells over-expressing Hexokinase2 (Hk2)/Pyruvate Kinase M2 (Pkm2)
2016-07-03 | E-GEOD-65246 | biostudies-arrayexpress
Project description:Myocarditis is a major health concern worldwide, often progressing to dilated cardiomyopathy (DCM) and sudden death, particularly in young individuals. However, the mechanisms driving the transition from acute myocarditis to inflammatory DCM (DCMi) remain unclear. Autoimmune responses, especially those involving interleukin (IL)-17A signaling, have been implicated, though the specific cellular targets and upstream regulators in the cardiac environment are not well understood. Here, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator in this process. Using the experimental autoimmune myocarditis (EAM) model, we show that TRIM21 expression is significantly upregulated in cardiac fibroblasts (CFs) during DCMi and upon IL-17A stimulation. Surprisingly, TRIM21 deficiency attenuated EAM progression, reducing inflammatory neutrophils and Ly6Chigh monocytes/macrophages infiltration. Bone marrow chimeric and IL-17A neutralization experiments confirmed TRIM21's role in CFs, where it promotes IL-17A signaling by facilitating TRAF3 degradation via K27-linked polyubiquitination. These findings identify TRIM21 as a new target in CFs and uncover a regulatory mechanism for IL-17A signaling, suggesting that therapies targeting TRIM21 may need to be adapted to different microenvironments.
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Project description:To investigate Trim21 knockdown on the gene expression of downstream effectors of MAPK and ERBB pathways, we established HPAC cell lines with Trim21 knockdown.
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Project description:Macrophage polarization followed by acute myocardial infarction (MI) is essential for the regulation of inflammation and scar formation. Tripartite motif-containing protein 21 (TRIM21), a member of E3 ubiquitin ligases, is a crucial mediator in the process of inflammation and heart failure. However, the potential roles of TRIM21 in modulating post-MI inflammation and macrophage polarization remain elusive. We detected that the levels of TRIM21 were significantly reduced in macrophages of WT mice after MI. In contrast, MI was ameliorated in TRIM21 knockout (TRIM21-/-) mice with improved cardiac remodeling, characterized by a marked decrease in mortality, increased wall thickness, and improved cardiac function in comparison with wild-type (WT) MI mice. Importantly, TRIM21 deficiency decreased the post-MI apoptosis and DNA damage in the hearts of mice, and the accumulation of M1 phenotype macrophages in infarcted hearts significantly decreased in TRIM21-/- mice compared with WT controls. Mechanistically, depletion of TRIM21 orchestrated the process of M1 macrophage polarization via a PI3K/Akt signaling pathway. Overall, these data reveal that TRIM21 drives the inflammatory response and cardiac remodeling after MI via stimulating M1 macrophage polarization through a PI3K/Akt signaling pathway.
2022-12-31 | GSE214696 | GEO
Project description:To investigate the biological function Trim21 in the colon cancer, we compared the gene expression profiles of colon tumor tissues from Trim21 +/+ and Trim21 -/- mice treated with the carcinogen azoxymethane (AOM) and the proinflammatory agent dextran sulfate sodium (DSS).
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