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Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-Tumor Immunity by Activating cGAS/STING Signaling

ABSTRACT: Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-Tumor Immunity by Activating cGAS/STING Signaling

PROVIDER: PRJNA1051588 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27187903_1.fastq.gz	Fastqsanger.gz
	SRR27187903_2.fastq.gz	Fastqsanger.gz
	SRR27187904_1.fastq.gz	Fastqsanger.gz
	SRR27187904_2.fastq.gz	Fastqsanger.gz
	SRR27187905_1.fastq.gz	Fastqsanger.gz

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Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-Tumor Immunity by Activating cGAS/STING Signaling

Project description:Hepatocellular carcinoma (HCC) is a highly lethal cancer for which current available treatment options have limited efficacy. Immunotherapy has emerged as a promising therapeutic option for HCC, yet resistance to immunotherapy is a major challenge. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a novel driver of immunotherapy resistance in HCC. We show that PRMT3 expression is induced by activated T cells in response to immune checkpoint blockade (ICB) via an interferon-gamma (IFN)STAT1 signaling pathway, and that high PRMT3 expression inversely correlates with tumor-infiltrating CD8+ T cells and predicts poor response to ICB in HCC patients. We demonstrate that genetic depletion and pharmacological inhibition of PRMT3 induce a profound influx of T cells into tumors and activate anti-tumor immunity to suppress HCC progression. Mechanistically, we demonstrate that PRMT3 methylates HSP60, a mitochondrial chaperone protein, at R446, and that this novel post-translational modification is required for HSP60 oligomerization and maintaining mitochondrial homeostasis. We reveal that targeting PRMT3-dependent HSP60-R446 methylation boosts anti-tumor immunity by disrupting mitochondrial function, increasing mitochondrial DNA (mtDNA) leakage, and activating the cGAS/STING pathway, a key innate immune sensor of cytosolic DNA. Importantly, we provide genetic and pharmacologic evidence that targeting PRMT3 enhances anti-PD1 efficacy and anti-tumor immunity in HCC mouse models. Our study identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

2024-05-29 | GSE249999 | GEO

Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling.

Project description:Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

| S-EPMC11387718 | biostudies-literature

Modelling HSP60 deficiency using an inducible transgenic HSP60 ATPase deficient mutant

Project description:To investigate the immediate effect of HSP60 dysfunction on mitochondrial functions, we induced the expression of a dominant-negative ATPase-deficient HSP60 mutant (HSP60-D423A) in HEK293 cells using tetracycline . Incorporation of HSP60-D423A subunits into HSP60 heptamer rings leads to dysfunction of the chaperonin complex. We titrated tetracycline levels to have a biologically relevant cellular model that can be monitored over time. Expression of the HSP60-D432A protein resulted in significantly reduced cell counts at 72 hours induction compared to uninduced and HSP60-WT co-expressing cells. To study the effects of onset of HSP60 deficiency, we monitored transcriptional changes using RNASeq.

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Expression profiles of E. coli groESL(-) cells expressing human Hsp60(wt)/Hsp10 or Hsp60-(p.Val98Ile)/Hsp10 operons

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Transcription profiling of E. coli groESL(-) cells expressing human Hsp60(wt)/Hsp10 or Hsp60-(p.Val98Ile)/Hsp10 operons

Project description:To identify regulatory responses that could give clues as to the cause(s) of the growth arrest observed in E. coli cells expressing mutant Hsp60-(p.Val98Ile) and Hsp10 versus cells expressing wild type Hsp60 and Hsp10, we performed microarray analyses. We reasoned that the decreased chaperonin activity of the Hsp60-(p.Val98Ile) protein would greatly impair or abolish folding of E. coli proteins that depend on chaperonin assistance. The resulting decreased levels of various activities may cause compensatory up-regulation or deregulation of genes. The transcriptomes of cells shifted to expression of the arabinose-inducible chaperonin operon with either the Hsp60-(p.Val98Ile) mutant or the wild type Hsp60 from the second plasmid were compared. RNA samples from three independent cultures expressing the mutant or two independent cultures expressing wild type Hsp60 were pooled, respectively. Experiment Overall Design: B178 (groELS)-deleted cells double-transformed with two plasmids harboring an IPTG-inducible operon with wild type human Hsp60 and Hsp10 and a second plasmid harboring an arabinose inducible operon with either Hsp60-(p.Val98Ile) and Hsp10 (mutant cells) or wild type Hsp60 and Hsp10 (wild type cells) were grown in dYT medium (21) supplemented with kanamycin (10 mg/L), ampicillin (100 mg/L) and IPTG (0.1mM) at 30Â°C in a shaking water bath. At OD536 â?? 0.1 bacteria were harvested by centrifugation at ambient temperature, resuspended in fresh medium, and 0.2% arabinose was added. Growth was continued at 30Â°C. After 10 hours 3ml samples were withdrawn and RNA was isolated. Experiment Overall Design: Two independent transformant clones of the wild type cells and three of the mutant cells were grown in this way. The RNA preps from the 2 wild type and the three mutant cells, respectively, were pooled, cDNA was synthesized, labelled and subjected to Affymetrix arrays.

2008-06-11 | E-GEOD-10974 | biostudies-arrayexpress

hsp60 gene sequence

Project description:hsp60 gene sequences of Helicobacter

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PRMT3-mediated cellular and molecular regulation in brain tumour stem cells.

Project description:Effect on gene expression profilng of BTSCs following PRMT3 inhibition with SGC707. To investigate the role of PRMT3 in regulating the cellular and molecular features of BTSCs, we performed RNA-seq using samples obtained from SGC707 treated versus XY1 treated GBM BTSCs.

2025-11-05 | GSE281186 | GEO

VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

Project description:Chemoresistance challenges the clinical application of most widely used platinum-based cancer chemotherapeutics which canonically function through inducing DNA damage. The DNA sensor cyclic GMP–AMP synthase (cGAS) connects genome instability to type I IFN response which confers vulnerability to platinum treatment. Here, by using a high throughput small-molecule-microarray-based screening of cGAS interacting compounds, we identified brivanib, known as an inhibitor of the vascular endothelial growth factor receptor (VEGFR), as a novel cGAS agonist. Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells indispensable of cGAS. Importantly, brivanib synergizes the effect of cisplatin in restricting the growth of xenografted Lewis Lung Cancer (LLC) cells by boosting CD8+ T cell response in a cGAS-dependent manner. Mechanistically, brivanib enhances the DNA binding affinity of cGAS by directly targeting leucine 495 of cGAS. Moreover, leucine 495 of cGAS is essential for brivanib-mediated promoting effect on cisplatin-mediated type I IFN response and inhibition of tumor growth. Clinically, higher expression of cGAS in tumor renders a more favorable response to platinum-based chemotherapeutic regimens and better prognosis in lung cancer patient. Taken together, our findings discover cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

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VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

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Effect of depletion of PRMT3 and IGF2BP1 on gene expression in PLC-8024 cells [PRMT3 IGF2BP1 KD RNA-seq]

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2023-02-28 | GSE206502 | GEO

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