Protein Arginine Methyltransferase 5 in T Lymphocyte Biology

Sengupta, Shouvonik; Kennemer, Austin; Patrick, Kristin L.; Tsichlis, Philip N.; Guerau-de-Arellano, Mireia

doi:10.1016/j.it.2020.08.007

Cited by 25 publications

(13 citation statements)

References 94 publications

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“…Several studies have demonstrated that PRMT5 deletion affects immune cell development. Deletion of PRMT5 in all cell types is disruptive to embryonic development, and T-cell-specific deletion of PRMT5 causes a decrease in the number of thymus iNK cells and peripheral CD4+ and CD8+ T cells ( 13 , 14 ). B cell-specific deletion of PRMT5 leads to reduced germinal center formation and causes B cell apoptosis ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

Zhou

Chen

et al. 2022

Front. Immunol.

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Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.

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Section: Introductionmentioning

confidence: 99%

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

Zhou

Chen

et al. 2022

Front. Immunol.

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“…Previous work from our lab and others has shown that PRMT5 is induced after CD4 Th cell activation/autoimmune responses, and that loss of protein arginine methyltransferase (PRMT)5 reduces TcR engagement-induced Th cell expansion and confers protection against the mouse model of Multiple Sclerosis, experimental autoimmune encephalomyelitis (EAE) [2][3][4] . However, the methylation targets of PRMT5 in T cells and associated molecular mechanisms are not well defined 5 .…”

Section: Introductionmentioning

confidence: 99%

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca²⁺/NFAT signaling

Sengupta

West

Sanghvi

et al. 2021

Preprint

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Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.

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“…Protein arginine methylation is an important post-translational modification that regulates signal transduction, DNA repair, RNA processing, protein-protein interactions and gene expression (10,11). Protein arginine methyl transferases (PRMTs) are classified into type I, II or III enzymes based on their ability to catalyze asymmetric dimethylation (ADM), symmetric dimethylation (SDM) or monomethylation of target proteins (11). Among PRMTs, PRMT1 and PRMT5 are responsible for the majority of ADM and SDM, respectively, in the cell.…”

Section: Introductionmentioning

confidence: 99%

PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

Lewis

Amici

Kim

et al. 2021

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Severe asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to a lack of mechanisms driving severe asthma phenotypes. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in asthmatic lungs. Here, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and granulocytic lung inflammation, pathology, airway remodeling and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, ROR-γt and Th17 responses, with PRMT5-dependent increases in ROR-γt agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.

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Protein Arginine Methyltransferase 5 in T Lymphocyte Biology

Cited by 25 publications

References 94 publications

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca²⁺/NFAT signaling

PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

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Protein Arginine Methyltransferase 5 in T Lymphocyte Biology

Cited by 25 publications

References 94 publications

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

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PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca²⁺/NFAT signaling