PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Panfil, Amanda R.; Al-Saleem, Jacob; Howard, Cory; Mates, Jessica M.; Kwiek, Jesse J.; Baiocchi, Robert A.; Green, Patrick L.

doi:10.3390/v8010007

Cited by 23 publications

(29 citation statements)

References 54 publications

(98 reference statements)

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“…Among PRMTs, PRMT5 appears to play a particularly relevant role in the regulation of cell death and malignant transformation processes in mouse and humans (35–38). Indeed, PRMT5 is up-regulated in various human lymphoid malignancies (39–41) and solid tumors (42–48) and promotes cancer cell proliferation and survival (38, 46, 49, 50). This has led to the development of selective PRMT5-inhibiting drugs such as CMP5 and EPZ015666 as a potential new therapy in cancer (43, 51, 52).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…They found that PRMT5 and HTLV-1 p30 had an additive inhibitory effect on HTLV-1 gene expression. However, reduced levels of PRMT5 did not significantly affect the ability of p30 to repress viral transcription, suggesting that the inhibitory role of p30 does not depend on PRMT5 [67].…”

Section: P30 Regulates Viral Latencymentioning

confidence: 88%

“…Using mass spectrometry, the arginine methyltransferase 5 (PRMT5) was recently identified as a p30 binding partner [56]. Panfil and colleagues investigated the role of PRMT5 in HTLV-1 infection and pathogenesis, showing that this cellular factor mediates cellular transformation and inhibits viral gene expression [67]. PRMT5 levels were found to be elevated in HTLV-1 transformed cells and knockdown of PRMT5 with shRNA or inhibition with a small molecule PRMT5 inhibitor increased HTLV-1 gene expression and decreased cellular proliferation and viability.…”

Section: P30 Regulates Viral Latencymentioning

confidence: 99%

p30 protein: a critical regulator of HTLV-1 viral latency and host immunity

et al. 2019

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The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated with the virus impress the great need for basic and translational research to prevent and treat HTLV-1 infection. The genome of the virus's most common subtype, HTLV-1A, encodes structural, enzymatic, and regulatory proteins that contribute to viral persistence and pathogenesis. Among these is the p30 protein encoded by the doubly spliced Tax-orf II mRNA, a nuclear/nucleolar protein with both transcriptional and post-transcriptional activity. The p30 protein inhibits the productive replication cycle via nuclear retention of the mRNA that encodes for both the viral transcriptional trans-activator Tax, and the Rex proteins that regulate the transport of incompletely spliced viral mRNA to the cytoplasm. In myeloid cells, p30 inhibits the PU-1 transcription factor that regulates interferon expression and is a critical mediator of innate and adaptive immunity. Furthermore, p30 alters gene expression, cell cycle progression, and DNA damage responses in T-cells, raising the hypothesis that p30 may directly contribute to T cell transformation. By fine-tuning viral expression while also inhibiting host innate responses, p30 is likely essential for viral infection and persistence. This concept is supported by the finding that macaques, a natural host for the closely genetically related simian T-cell leukemia virus 1 (STLV-1), exposed to an HTLV-1 knockout for p30 expression by a single point mutation do not became infected unless reversion and selection of the wild type HTLV-1 genotype occurs. All together, these data suggest that inhibition of p30 may help to curb and eventually eradicate viral infection by exposing infected cells to an effective host immune response.

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“…The pLenti-puro vector expressing HA-tagged T592A and HD/RN SAMHD1 mutant constructs were generated using a Quikchange mutagenesis kit (Agilent Technologies) (27). The HTLV-1-LTR luciferase reporter plasmid and pcTax were provided by Patrick Green (The Ohio State University) (71). The HIV-1 FF-luc (pGL3-LTR-luc) was provided by Jian-Hua Wang (Pasteur Institute of Shanghai) (55).…”

Section: Methodsmentioning

confidence: 99%

SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4⁺ T-cells

et al. 2018

Preprint

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PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Cited by 23 publications

References 54 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

p30 protein: a critical regulator of HTLV-1 viral latency and host immunity

SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4⁺ T-cells

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PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Cited by 23 publications

References 54 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

p30 protein: a critical regulator of HTLV-1 viral latency and host immunity

SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4+ T-cells

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SAMHD1 Impairs HIV-1 Gene Expression and Reactivation of Viral Latency in CD4⁺ T-cells