Protein arginine methylation: a new handle on T lymphocytes?

Parry, Richard V.; Ward, Stephen G.

doi:10.1016/j.it.2010.01.006

Cited by 36 publications

(33 citation statements)

References 42 publications

(50 reference statements)

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“…As MTA is a potent protein methylation inhibitor, 23,33,48 and there are several reports showing that protein methylation plays a so far underestimated role in T cell stimulation, [73][74][75][76] we investigated whether other synthetic protein methylation inhibitors could mimic the impact of MTA on T cells. Indeed, 3 0 -deazaadenosine 40 and adenosine-2,3-dialdehyde 77 suppressed T cells in a similar manner (data not shown), i.e.…”

Section: Discussionmentioning

confidence: 99%

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

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The immunosuppressive tumor microenvironment represents one of the main obstacles for immunotherapy of cancer. The tumor milieu is among others shaped by tumor metabolites such as 5 0 -deoxy-5 0 -methylthioadenosine (MTA). Increased intratumoral MTA levels result from a lack of the MTAcatabolizing enzyme methylthioadenosine phosphorylase (MTAP) in tumor cells and are found in various tumor entities. Here, we demonstrate that MTA suppresses proliferation, activation, differentiation, and effector function of antigen-specific T cells without eliciting cell death. Conversely, if MTA is added to highly activated T cells, MTA exerts cytotoxic effects on T cells. We identified the Akt pathway, a critical signal pathway for T cell activation, as a target of MTA, while, for example, p38 remained unaffected. Next, we provide evidence that MTA exerts its immunosuppressive effects by interfering with protein methylation in T cells. To confirm the relevance of the suppressive effects of exogenously added MTA on human T cells, we used an MTAP-deficient tumor cell-line that was stably transfected with the MTAPcoding sequence. We observed that T cells stimulated with MTAP-transfected tumor cells revealed a higher proliferative capacity compared to T cells stimulated with Mock-transfected cells. In conclusion, our findings reveal a novel immune evasion strategy of human tumor cells that could be of interest for therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

et al. 2016

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“…There is an emerging body of evidence that PRMT enzymes play an important pathogenic role in inflammation (43). For example, both PRMT1 and PRMT4 have been implicated in the inflammatory response in association with NF-B (17,24).…”

Section: Discussionmentioning

confidence: 99%

HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Bandyopadhyay

Harris

Adams

et al. 2012

Molecular and Cellular Biology

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The induction of proinflammatory proteins in stimulated endothelial cells (EC) requires activation of multiple transcription programs. The homeobox transcription factor HOXA9 has an important regulatory role in cytokine induction of the EC-leukocyte adhesion molecules (ELAM) E-selectin and vascular cell adhesion molecule 1 (VCAM-1). However, the mechanism underlying stimulus-dependent activation of HOXA9 is completely unknown. Here, we elucidate the molecular mechanism of HOXA9 activation by tumor necrosis factor alpha (TNF-␣) and show an unexpected requirement for arginine methylation by protein arginine methyltransferase 5 (PRMT5). PRMT5 was identified as a TNF-␣-dependent binding partner of HOXA9 by mass spectrometry. Small interfering RNA (siRNA)-mediated depletion of PRMT5 abrogated stimulus-dependent HOXA9 methylation with concomitant loss in E-selectin or VCAM-1 induction. Chromatin immunoprecipitation analysis revealed that PRMT5 is recruited to the E-selectin promoter following transient HOXA9 binding to its cognate recognition sequence. PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, an event essential for E-selectin induction. In summary, PRMT5 is a critical coactivator component in a newly defined, HOXA9-containing transcription complex. Moreover, stimulus-dependent methylation of HOXA9 is essential for ELAM expression during the EC inflammatory response.

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“…Regarding the upstream mechanism of the PRMT upregulation, we conjectured that Th2 cytokines probably play a crucial role because T cells may control PRMT activity through increasing cytokine production (15,24). IL-4 is one of the most important players in airway inflammation and can enhance the expression of eotaxin-1 in lung stable cells (25).…”

Section: Discussionmentioning

confidence: 99%

“…PRMT1, on the one hand, can catalyze the methylation of histones H4 at arginine 3 (H4R3), which acts as a part of the histone code to regulate gene expression (11)(12)(13); on the other hand, recent studies have revealed that a plethora of proteins with methylated arginine residues catalyzed by PRMT1 implicate in a variety of cellular processes. For example, PRMT1 enhances gene transcription by methylating N-terminal arginine residues in NFAT-interacting protein 45, which heterodimerizes with NFAT and then enhances NFAT, driving cytokine production upon TCR signaling of T cells (14,15).…”

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confidence: 99%

Upregulated Protein Arginine Methyltransferase 1 by IL-4 Increases Eotaxin-1 Expression in Airway Epithelial Cells and Participates in Antigen-Induced Pulmonary Inflammation in Rats

Sun

Yang

Zhong

et al. 2012

The Journal of Immunology

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Protein arginine methyltransferases (PRMTs), catalyzing methylation of both histones and other cellular proteins, have emerged as key regulators of various cellular processes. This study aimed to identify key PRMTs involved in Ag-induced pulmonary inflammation (AIPI), a rat model for asthma, and to explore the role of PRMT1 in the IL-4–induced eosinophil infiltration process. E3 rats were i.p. sensitized with OVA/alum and intranasally challenged with OVA to induce AIPI. The expressions of PRMT1–6, eotaxin-1, and CCR3 in lungs were screened by real-time quantitative PCR. Arginine methyltransferase inhibitor 1 (AMI-1, a pan-PRMT inhibitor) and small interfering RNA–PRMT1 were used to interrupt the function of PRMT1 in A549 cells. In addition, AMI-1 was administrated intranasally to AIPI rats to observe the effects on inflammatory parameters. The results showed that PRMT1 expression was mainly expressed in bronchus and alveolus epithelium and significantly upregulated in lungs from AIPI rats. The inhibition of PRMTs by AMI-1 and the knockdown of PRMT1 expression were able to downregulate the expressions of eotaxin-1 and CCR3 with the IL-4 stimulation in the epithelial cells. Furthermore, AMI-1 administration to AIPI rats can also ameliorate pulmonary inflammation, reduce IL-4 production and humoral immune response, and abrogate eosinophil infiltration into the lungs. In summary, PRMT1 expression is upregulated in AIPI rat lungs and can be stimulated by IL-4. Intervention of PRMT1 activity can abrogate IL-4–dependent eotaxin-1 production to influence the pulmonary inflammation with eosinophil infiltration. The findings may provide experimental evidence that PRMT1 plays an important role in asthma pathogenesis.

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Protein arginine methylation: a new handle on T lymphocytes?

Cited by 36 publications

References 42 publications

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Upregulated Protein Arginine Methyltransferase 1 by IL-4 Increases Eotaxin-1 Expression in Airway Epithelial Cells and Participates in Antigen-Induced Pulmonary Inflammation in Rats

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