Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways
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ABSTRACT:
PROVIDER: PRJNA1104167 | ENA |
REPOSITORIES: ENA
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Project description:This study investigated the mechanisms underlying photosensitivity in patients with systemic lupus erythematosus (SLE), focusing on the role of type I interferons (IFNs) and TRIM21, an autoantigen in SLE. Through experiments on mice exposed to ultraviolet light B (UVB), we demonstrate that TRIM21 deficiency leads to exacerbated systemic inflammation and IFN-driven responses following UVB exposure, mimicking aspects of SLE pathology. Specifically, we observe enhanced expression of IFN-stimulated genes (ISGs), increased levels of inflammatory chemokines, and elevated IgG deposition in the skin of UVB-exposed Trim21-/- mice. Mechanistic investigations reveal that TRIM21 restrains IFN induction by regulating the STING pathway, impacting the stability of proteins involved in RNA/DNA sensing and IFN responses. These findings shed light on the protective role of TRIM21 against UVB-induced systemic disease in SLE, offering insights into its potential as a therapeutic target to mitigate disease flares and activity in SLE patients.
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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:Ultraviolet B (UVB) irradiation has strong biological effects and modulates the expression of many genes. However, the major biological themes affected by UVB remain poorly understood. This work employs a loop-designed microarray approach and applies a log linear model along with multiple hypotheses testing to identify differentially regulated genes at 4, 8, 16, or 24 hours following UVB irradiation. The most prominent biological themes in lists of differentially regulated gene sets were extracted by functional enrichment analysis using DAVID bioinformatics resources 2007. By this approach, we identify that genes that participate in two prime cellular processes – the ribosome pathway and the oxidative phosphorylation pathway - are persistently activated over a period of 24 hours following UVB irradiation. Microarray results were further verified by both mitochondrial activity assay and real-time PCR analysis. These data suggest that the persistent activation of ribosome and oxidative phosphorylation pathways may have a key role in UVB-induced cellular responses. For the first time, the specific cellular pathways that respond to UVB irradiation consistently and persistently can be delineated confidently using a loop-designed microarray approach and functional bioinformatics analysis. The results of this study offer further insight into UVB-induced stress responses. Keywords: UVB, cDNA microarray, loop design, KEGG pathway
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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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Project description:This study comprehensively investigates the photoprotective effects of aloin against UVB-induced damage in HaCaT cells, elucidating its antioxidant capacity and its role in preventing cellular apoptosis. The proteomic effect of 50 μg/mL aloin on HaCaT cell damage induced by UVB was evaluated through comparative protein expression. Compared to control cells, UVB irradiation significantly altered protein expression in HaCaT cells, with 64 proteins upregulated and 236 proteins downregulated. In cells treated with both UVB and aloin, 79 proteins were upregulated and 84 proteins were downregulated compared to the UVB-only group. Proteomic analysis showed that aloin modulated the expression of proteins involved in critical signaling pathways, including PI3K-Akt, p53, TGF-β and pathways in cancer, promoting cell survival. Aloin upregulated proteins associated with cell cycle regula-tion and antioxidant responses, such as CCND3, GSTM4, GNA12, SKIL, YWHAZ, and PKN3 while downregulating pro-apoptotic protein FOXO3.
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Project description:In order to define the cohort of genes whose expression is regulated by TRIM21 in CRC, we constructed HCT8 cells stably infected with lentivirus carrying control shRNA (shNC) or TRIM21 shRNA (sh1). Subsequently, total RNA was isolated and then performed transcriptome RNA sequence.
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Project description:Effect of Trim21 knockdown on MAPK and ERBB signaling pathways
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Project description:Most systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.
2020-04-13 | GSE148535 | GEO
Project description:Bortezomib (bort) is an effective therapeutic agent for multiple myeloma (MM) patients; however, the majority of patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, while TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phospho-proteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated pro-survival autophagy. Our results provided that TRIM21 KD MM cell lines induced pro-survival autophagy after bort treatment, and suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of ATG5 restored bort sensitivity. Indeed, autophagy-related gene 5 (ATG5) expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the anti-myeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approaches.
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