PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Snyder, Katiri; Zitzer, Nina C.; Gao, Yandi; Choe, Hannah; Sell, Natalie E.; Neidemire-Colley, Lotus; Ignaci, Anora; Kale, Charuta; Devine, Raymond D.; Abad, Maria G; Pietrzak, Maciej; Wang, Min; Lin, Hong; Zhang, Yang W.; Behbehani, Gregory K.; Jackman, Jane E.; Garzon, Ramiro; Vaddi, Kris; Baiocchi, Robert A.; Ranganathan, Parvathi

doi:10.1172/jci.insight.131099

Cited by 27 publications

(21 citation statements)

References 97 publications

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“…Together with the decreased expression of the proinflammatory cytokines IL-12p70, TNF-α, and IL-6 detected in our results, we observed a widespread effect of PRMT5 inhibition on DC activation and maturation after LPS stimulation. Previous studies have reported a key role for posttranslational modification of PRMT5 in promoting T cell function, such as T cell activation (45), maintenance (22,23), expansion (24), and differentiation (46), and our results further support those findings by providing insights into the role of PRMT5 in DCs.…”

Section: Discussionsupporting

confidence: 89%

“…PRMT5 has been shown to be upregulated in inflammatory diseases, such as Crohn's disease, rheumatoid arthritis and endothelial cell inflammation, and inhibition of PRMT5 reduces inflammation (19)(20)(21). Moreover, PRMT5 promotes T cell maintenance in vitro (22,23). PRMT5 inhibition protects mice from autoimmune diseases and transplant rejection (23)(24)(25), and circ-PRMT5 has been reported to regulate tumor cell metabolism by enhancing glycolysis activity (26).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, PRMT5 promotes T cell maintenance in vitro (22,23). PRMT5 inhibition protects mice from autoimmune diseases and transplant rejection (23)(24)(25), and circ-PRMT5 has been reported to regulate tumor cell metabolism by enhancing glycolysis activity (26). However, whether PRMT5 modulates DCs through metabolism has not yet been studied.…”

Section: Introductionmentioning

confidence: 99%

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PRMT5 inhibition modulates murine dendritic cells activation by inhibiting the metabolism switch: a new therapeutic target in periodontitis

Mi¹,

Qiao²,

Zhang³

et al. 2021

Ann Transl Med

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Background: Protein arginine methyltransferase 5 (PRMT5) catalyzes the methylation of arginine residues in multiple proteins. Recent reports have highlighted the anti-inflammatory role of PRMT5. Dendritic cells (DCs) are well-known professional antigen-presenting cells that are crucial for immune response initiation. However, whether PRMT5 participates in DC immunity processes is unknown.Methods: In an in vitro experiment, a PRMT5 inhibitor (EPZ015666) was used to inhibit PRMT5 expression, and lipopolysaccharide (LPS) stimulation was applied to mimic the inflammation context. Proinflammatory cytokine production, interferon-stimulated genes (ISGs), costimulatory molecules, major histocompatibility complex (MHC) expression and DC metabolism were measured following PRMT5 inhibition and LPS stimulation. In an in vivo study, we first tested PRMT5 mRNA and protein expression in a BALB/c mouse ligature-induced periodontitis model. Then, we evaluated changes in periodontal tissue and DC migration to cervical lymph nodes after local treatment with the PRMT5 inhibitor. Results:The in vitro results revealed that PRMT5 inhibition attenuated DC activation and maturation by inhibiting the expression of proinflammatory cytokines, ISGs, costimulatory molecules, and MHC induced by LPS stimulation. We also found that inhibition of PRMT5 blocked the DC metabolic switch to glycolysis.In the in vivo study, we found that PRMT5 inhibition reversed the severity of the lesions and slowed the migration of DCs to cervical lymph nodes. Conclusions:The results show a critical role of PRMT5 in the control of DC activation through inhibition of the metabolic switch and indicate that PRMT5 is a promising therapeutic target in periodontitis.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PRMT5 inhibition modulates murine dendritic cells activation by inhibiting the metabolism switch: a new therapeutic target in periodontitis

Mi¹,

Qiao²,

Zhang³

et al. 2021

Ann Transl Med

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“…Further, PRMT5 promotes Th17 differentiation by activation of SREBP1-choresterol pathway along the RORγt axis [101]. PRMT5 induction and subsequent Th1 and Th17 differentiation exemplify the pathological roles played by PRMT5 in autoimmune disorders, experimental autoimmune encephalomyelitis (EAE) and acute graft-versus-host diseases (aGVHD) [98,101,102].…”

Section: Prmt5 In Tumor Immunitymentioning

confidence: 99%

PRMT5 function and targeting in cancer

Kim¹,

Ronai²

2020

CST

120

108

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Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapyresponse. Here we discuss the function of PRMT5, a member of the nine-member PRMT family, in controlling oncogenic processes including tumor intrinsic, as well as extrinsic microenvironmental signaling pathways. We discuss PRMT5 effect on histone methylation and methylation of regulatory proteins including those involved in RNA splicing, cell cycle, cell death and metabolic signaling. In all, we highlight the importance of PRMT5 regulation and function in cancer, which provide the foundation for therapeutic modalities targeting PRMT5.

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“…Finally, using a CRISPR-screening approach, we have found that in the presence of PRMT5 inhibitors cells are sensitized to PRMT1 and CARM1 loss [ 162 ]. Thus, it may be important to evaluate the effects of a CARM1 inhibitor (GSK3359088) [ 163 ] and a Type I PRMT inhibitor (GSK3368715) [ 161 ] for their ability to retard the growth of tumors with elevated PRMT5–SND1 signaling.…”

Section: Targeting Elevated Snd1 Levels With Prmt5 Inhibitorsmentioning

confidence: 99%

The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma

2021

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Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor domain-containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy.

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PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Cited by 27 publications

References 97 publications

PRMT5 inhibition modulates murine dendritic cells activation by inhibiting the metabolism switch: a new therapeutic target in periodontitis

PRMT5 inhibition modulates murine dendritic cells activation by inhibiting the metabolism switch: a new therapeutic target in periodontitis

PRMT5 function and targeting in cancer

The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma

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