Tumor Necrosis Factor (TNF)-α Induction of CXCL10 in Endothelial Cells Requires Protein Arginine Methyltransferase 5 (PRMT5)-mediated Nuclear Factor (NF)-κB p65 Methylation

Harris, Daniel P.; Bandyopadhyay, Smarajit; Maxwell, Tyler; Willard, Belinda; DiCorleto, Paul E.

doi:10.1074/jbc.m114.547349

Cited by 72 publications

(67 citation statements)

References 41 publications

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“…While future studies will be required to clarify the extent to which these pathways affect PRMT5 up-regulation in T cells, NF-κB appears to play a major role in TCR-induced PRMT5 expression in human Th1, but not Th2, cells. Additionally, several studies have shown that PRMT5 activates NF-κB signaling through arginine methylation of p65 (56, 66–68), suggesting that the NF-κB-PRMT5 signaling axis could involve a positive feedback loop. Additional studies are required to validate this feedback loop and evaluate its role in T cells.…”

Section: Discussionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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In the autoimmune disease multiple sclerosis (MS) and its animal model Experimental Autoimmune Encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the Protein Arginine Methyl Transferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. Here, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently up-regulated during maximal proliferation of both mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in Delayed Type Hypersensitivity (DTH) and clinical disease in Experimental Autoimmune Encephalomyelitis (EAE) mouse models. These data implicate PRMT5 in regulation of adaptive memory T helper cell responses and suggest PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease.

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Section: Discussionmentioning

confidence: 99%

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Webb

Amici

Jablonski

et al. 2017

The Journal of Immunology

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“…We demonstrate that PRMT1 forms a cellular complex with RelA and asymmetrically dimethylates the conserved R30 residue in the RelA DNA-binding L1 loop. The asymmetric dimethylation of RelA by PRMT1 is enhanced after prolonged treatment of cells with TNFα and, in contrast to the symmetric modification (16,17), negatively regulates the DNA binding and transcriptional activity of RelA. We also find that down-regulation of PRMT1 enhances the expression of NF-κB target genes after TNFα stimulation by facilitating RelA recruitment to specific promoters.…”

Section: Significancesupporting

confidence: 51%

“…Several histone lysine methyltransferases, including SET7/9, SETD6, and NSD1, have been shown to both positively and negatively regulate NF-κB through direct monomethylation or dimethylation of distinct lysine residues in RelA (12)(13)(14)(15). Recent studies also have shown that RelA is methylated by the type II protein arginine methyltransferase 5 (PRMT5), which catalyzes the synthesis of ω-N Gmonomethylarginine (MMA) and symmetric ω-N G ,N′ G -dimethylarginine (SDMA) (16,17).…”

mentioning

confidence: 99%

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Reintjes

Fuchs

Kremser

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB-activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA-NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.arginine methylation | genes | TNFα | NF-κB

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“…Some nonhistone proteins are also directly methylated by PRMT5, resulting in tumor progression (41)(42)(43). In our study, when we used GST-PRMT5 as the bait to find its possible partners ($72 kDa), mSREBP1a had the highest number of identified peptides via MS assay.…”

Section: Discussionmentioning

confidence: 93%

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth

Liu

Zhao

et al. 2016

Cancer Research

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Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3b, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin-proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism.

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Tumor Necrosis Factor (TNF)-α Induction of CXCL10 in Endothelial Cells Requires Protein Arginine Methyltransferase 5 (PRMT5)-mediated Nuclear Factor (NF)-κB p65 Methylation

Cited by 72 publications

References 41 publications

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth

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