NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms

Webb, Lindsay M.; Narvaez-Miranda, Janiret; Amici, Stephanie A.; Sengupta, Shouvonik; Nagy, Gregory; Guerau-de-Arellano, Mireia

doi:10.3389/fimmu.2019.00524

Cited by 22 publications

(18 citation statements)

References 68 publications

(100 reference statements)

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“…5D ). Furthermore, the levels of downstream targets of NF-κB, including MMP9 31 , c-myc 32 , CyclinD1 33 , and CDK6 34 , were dramatically reduced after FKBP4 depletion in H1975 cells (Fig. 5E ).…”

Section: Resultsmentioning

confidence: 97%

FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling

et al. 2021

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FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKβ, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. Collectively, FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to potentiate the transcriptional activity and nuclear translocation of NF-κB, thereby promoting LUAD progression. Our findings suggest that FKBP4 may function as a prognostic biomarker of LUAD and provide a newly mechanistic insight into modulating IKK/NF-κB signaling.

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Section: Resultsmentioning

confidence: 97%

FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling

et al. 2021

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“…Cell Cycle Progression at the G1/S Checkpoint PRMT5 promotes proliferation in mouse and human T helper (Th) cells (16,17,20), but the underlying mechanism is not clearly understood. To investigate this, we used myelin-specific MBP TCR transgenic mouse Th1 cells.…”

Section: Prmt5 Inhibition Arrests Tcr-inducedmentioning

confidence: 99%

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

2021

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Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates proteins and promotes T cell proliferation. However, the mechanism behind PRMT5-mediated control of T cell proliferation and whether PRMT5 contributes to diseases severity is unclear. Here, we evaluated the role of PRMT5 on cyclin/cdk pairs and cell cycle progression, as well as PRMT5’s link to disease severity in an animal model of relapsing-remitting MS. Treatment of T helper 1 (mTh1) cells with the selective PRMT5 inhibitor, HLCL65, arrested activation-induced T cell proliferation at the G1 stage of the cell cycle, suggesting PRMT5 promotes cell cycle progression in CD4+ T cells. The Cyclin E1/Cdk2 pair promoting G1/S progression was also decreased after PRMT5 inhibition, as was the phosphorylation of retinoblastoma. In the SJL mouse relapsing-remitting model of MS, the highest PRMT5 expression in central nervous system-infiltrating cells corresponded to peak and relapse timepoints. PRMT5 expression also positively correlated with increasing CD4 Th cell composition, disease severity and Cyclin E1 expression. These data indicate that PRMT5 promotes G1/S cell cycle progression and suggest that this effect influences disease severity and/or progression in the animal model of MS. Modulating PRMT5 levels may be useful for controlling T cell expansion in T cell-mediated diseases including MS.

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“…We recently reported that PRMT5 is induced after T cell activation and that its induction is controlled by NF-κB/MYC/mTOR signaling (8,9). PRMT5's SDM mark also has been shown to be dynamically regulated in T cells (10), suggesting that it contributes to the T cell activation process.…”

Section: Introductionmentioning

confidence: 99%

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity

Webb¹,

Sengupta²,

Edell³

et al. 2020

Journal of Clinical Investigation

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NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms

Cited by 22 publications

References 68 publications

FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling

FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity

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