NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00524/full |
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| author | Lindsay M. Webb Lindsay M. Webb Janiret Narvaez Miranda Stephanie A. Amici Shouvonik Sengupta Shouvonik Sengupta Gregory Nagy Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano |
| author_facet | Lindsay M. Webb Lindsay M. Webb Janiret Narvaez Miranda Stephanie A. Amici Shouvonik Sengupta Shouvonik Sengupta Gregory Nagy Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano |
| author_sort | Lindsay M. Webb |
| collection | DOAJ |
| description | Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory Th1 cells and during EAE. However, the mechanisms driving PRMT5 protein induction and repression as T cells expand and return to resting is currently unknown. Here, we used naive mouse and memory mouse and human Th1/Th2 cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Initial activation of naive mouse T cells resulted in NF-κB-dependent transient Prmt5 transcription and NF-κB, mTOR and MYC-dependent PRMT5 protein induction. In murine memory Th cells, transcription and miRNA loss supported PRMT5 induction to a lesser extent than in naive T cells. In contrast, NF-κB/MYC/mTOR-dependent non-transcriptional PRMT5 induction played a major role. These results highlight the importance of the NF-κB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS. |
| first_indexed | 2024-12-21T03:32:15Z |
| format | Article |
| id | doaj.art-ee1831e114f8473083756e99a29a3800 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T03:32:15Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ee1831e114f8473083756e99a29a38002022-12-21T19:17:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00524428507NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional MechanismsLindsay M. Webb0Lindsay M. Webb1Janiret Narvaez Miranda2Stephanie A. Amici3Shouvonik Sengupta4Shouvonik Sengupta5Gregory Nagy6Mireia Guerau-de-Arellano7Mireia Guerau-de-Arellano8Mireia Guerau-de-Arellano9Mireia Guerau-de-Arellano10Division of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United StatesBiomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, United StatesDivision of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United StatesDivision of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United StatesDivision of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United StatesBiomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, United StatesBiomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, United StatesDivision of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United StatesInstitute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United StatesDepartment of Neuroscience, The Ohio State University, Columbus, OH, United StatesMultiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory Th1 cells and during EAE. However, the mechanisms driving PRMT5 protein induction and repression as T cells expand and return to resting is currently unknown. Here, we used naive mouse and memory mouse and human Th1/Th2 cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Initial activation of naive mouse T cells resulted in NF-κB-dependent transient Prmt5 transcription and NF-κB, mTOR and MYC-dependent PRMT5 protein induction. In murine memory Th cells, transcription and miRNA loss supported PRMT5 induction to a lesser extent than in naive T cells. In contrast, NF-κB/MYC/mTOR-dependent non-transcriptional PRMT5 induction played a major role. These results highlight the importance of the NF-κB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS.https://www.frontiersin.org/article/10.3389/fimmu.2019.00524/fullPRMT5T cellsignalingmultiple sclerosisnaivememory |
| spellingShingle | Lindsay M. Webb Lindsay M. Webb Janiret Narvaez Miranda Stephanie A. Amici Shouvonik Sengupta Shouvonik Sengupta Gregory Nagy Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano Mireia Guerau-de-Arellano NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms Frontiers in Immunology PRMT5 T cell signaling multiple sclerosis naive memory |
| title | NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms |
| title_full | NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms |
| title_fullStr | NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms |
| title_full_unstemmed | NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms |
| title_short | NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms |
| title_sort | nf κb mtor myc axis drives prmt5 protein induction after t cell activation via transcriptional and non transcriptional mechanisms |
| topic | PRMT5 T cell signaling multiple sclerosis naive memory |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00524/full |
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