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EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

ABSTRACT: EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

PROVIDER: PRJNA1052586 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27205588_1.fastq.gz	Fastqsanger.gz
	SRR27205588_2.fastq.gz	Fastqsanger.gz
	SRR27205589_1.fastq.gz	Fastqsanger.gz
	SRR27205589_2.fastq.gz	Fastqsanger.gz

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EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

Project description:While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells is poorly understood. Here, we identified EPDR1 as an important intrinsic tumor regulator of PD-L1 expression and the antitumor T-cell response that inhibits TRIM21-dependent ubiquitylation of IKBKB. Mechanistically, EPDR1 binds to TRIM21 and disrupts its interaction with IKBKB, which suppresses the ubiquitylation and autophagosome degradation of the IKBKB protein and thus enhances NF-κB-mediated transcriptional activation of PD-L1. We further confirmed through a mouse liver cancer model that EPDR1 mediates the exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals an unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression, suggesting that targeting EPDR1-TRIM21 is a potential strategy for cancer immunotherapy.

2024-06-29 | GSE250169 | GEO

EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-b

Project description:While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression.

| S-SCDT-10_1038-S44318-024-00201-6 | biostudies-other

Effect of Trim21 knockdown on MAPK and ERBB signaling pathways

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.

2023-08-08 | GSE208568 | GEO

TRIM21 aggravates cardiac injury after myocardial infarction via promoting M1 macrophage polarization

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

IFN gamma signaling in cytotoxic T cells restricts antitumor responses by inhibiting the maintenance and clonality of intra-tumoral stem-like T cells

Project description:IFN gamma signaling in cytotoxic T cells restricts antitumor responses by inhibiting the maintenance and clonality of intra-tumoral stem-like T cells

2022-12-16 | GSE221118 | GEO

Pa01c cells stable expressing a scramble or shRNA against TRIM21

Project description:We make Pa01c cells stable expressing a scramble or shRNA against TRIM21 and performed bulk scRNASeq to assess transcriptomic changes Pa01c cells

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TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting pro-survival autophagy

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.

2023-10-24 | PXD042004 | Pride

TRIM21 knockout mouse livers show enhanced antioxidant capacity and decreased compensatory proliferation

Project description:Acute response to diethylnitrosamine treatment in TRIM21 wild-type and knockout mice were compared and differentially expressed genes were inendified at 48 hours

2021-04-14 | GSE164369 | GEO

Histone H2B ubiquitylation and H3 lysine 4 methylation prevent ectopic silencing of euchromatic loci important for the cellular response to heat

Project description:In Saccharomyces cerevisiae, ubiquitylation of histone H2B signals methylation of histone H3 at lysine residues 4 (K4) and 79. These modifications occur at active genes but are believed to stabilize silent chromatin by limiting movement of silencing proteins away from heterochromatin domains. In the course of studying atypical phenotypes associated with loss of H2B ubiquitylation/H3K4 methylation, we discovered that these modifications are also required for cell wall integrity at high temperatures. We identified the silencing protein Sir4 as a dosage-suppressor of loss of H2B ubiquitylation, and showed that elevated Sir4 expression suppresses cell wall integrity defects by inhibiting the function of the Sir silencing complex. Using comparative transcriptome analysis, we identified a set of euchromatic genes - enriched in those required for cellular response to heat - whose expression is attenuated by loss of H2B ubiquitylation, but restored by disruption of Sir protein function. Finally, using DNA adenine methyltransferase identification, we found that Sir3 and Sir4 associate with genes that are silenced in the absence of H3K4 methylation. Our data reveal that H2B ubiquitylation/H3K4 methylation play an important role in limiting ectopic association of silencing proteins with euchromatic genes important for cell wall integrity and the response to heat. The transcriptome of four strains, wildtype, htbK123R, sir4delta,and htbK123R sir4delta, were sequenced using Illumina sequencing technology

2011-12-02 | E-GEOD-27934 | biostudies-arrayexpress

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