Dataset Information

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca²⁺/NFAT Signaling.

ABSTRACT: Protein arginine methyltransferase (PRMT) 5 is the type 2 methyltransferase catalyzing symmetric dimethylation 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, the animal model of multiple sclerosis. However, the mechanisms by which PRMT5 modulates 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 in activated mouse T cells and identify several targets of PRMT5 symmetric dimethylation involved in splicing. In addition, we find a possible link between PRMT5-mediated alternative splicing of transient receptor potential cation channel subfamily M member 4 (Trpm4) 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.

SUBMITTER: Sengupta S

PROVIDER: S-EPMC9377504 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca<sup>2+</sup>/NFAT Signaling.

Sengupta Shouvonik S West Kelsi O KO Sanghvi Shridhar S Laliotis Georgios G Agosto Laura M LM Lynch Kristen W KW Tsichlis Philip N PN Singh Harpreet H Patrick Kristin L KL Guerau-de-Arellano Mireia M

ImmunoHorizons 20211029 10

Protein arginine methyltransferase (PRMT) 5 is the type 2 methyltransferase catalyzing symmetric dimethylation 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, the animal model of multiple sclerosis. However, the mechanisms by which PRMT5 modulates Th cell proliferation are still not completely understood, and neither are the methylation targets ...[more]

PMID: 34716181

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Project description:BackgroundRegorafenib has been approved for second-line treatment of hepatocellular carcinoma (HCC) following sorafenib failure, but resistance to targeted therapy remains a major challenge. Enhancing the therapeutic sensitivity of HCC cells to regorafenib is crucial for improving treatment outcomes. This study aims to elucidate the role of PRMT5 in HCC and its impact on regorafenib sensitivity. Specifically, it focuses on the regulatory relationship between PRMT5 and RPL14, investigating their influence on DNA damage repair and drug resistance mechanisms in HCC.MethodsA stable PRMT5-overexpressing HCC cell line was constructed via lentiviral infection. Immunoprecipitation was employed to examine whether PRMT5 catalyzes the symmetric dimethylation of RPL14 at arginine residues. Western blot (WB) was used to assess changes in DNA damage markers (γ-H2AX) and DNA repair markers (RAD51) after RPL14 knockdown. Huh7 cells with PRMT5 overexpression, RPL14 knockdown, and combined PRMT5 overexpression and RPL14 knockdown were treated with regorafenib. DNA damage repair-related factors were analyzed using WB and immunofluorescence.ResultsMass spectrometry and immunoprecipitation confirmed the interaction between PRMT5 and RPL14, with PRMT5 catalyzing symmetric dimethylation of RPL14. RPL14 knockdown inhibited HCC cell proliferation, increased sensitivity to regorafenib, and disrupted DNA damage repair, while overexpression had the opposite effect. Regorafenib-treated PRMT5-overexpressing cells showed reduced γ-H2AX expression and improved survival, whereas RPL14 knockdown enhanced γ-H2AX levels and decreased survival. Notably, simultaneous PRMT5 overexpression and RPL14 knockdown significantly elevated γ-H2AX expression compared to PRMT5 overexpression alone, leading to reduced cell viability. These results suggest that PRMT5 modulates DNA damage repair through RPL14, influencing the sensitivity of HCC cells to regorafenib.ConclusionsPRMT5-mediated symmetric dimethylation of RPL14 stabilizes the protein, promoting DNA damage repair and contributing to regorafenib resistance in HCC. RPL14 plays a key role in PRMT5-driven enhancement of DNA damage repair and reduced drug sensitivity, identifying RPL14 as a potential therapeutic target to overcome regorafenib resistance in HCC.

Dataset Information

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca²⁺/NFAT Signaling.

Publications

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca<sup>2+</sup>/NFAT Signaling.

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Dataset Information

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca2+/NFAT Signaling.

Publications

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca<sup>2+</sup>/NFAT Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca²⁺/NFAT Signaling.