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Role of Protein Arginine Methyltransferase 5 in T cell metabolism and alternative splicing

Sengupta, Shouvonik
http://orcid.org/0000-0003-1680-1315
http://rave.ohiolink.edu/etdc/view?acc_num=osu1638440840794086

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the brain and spinal cord leading to demyelination. Symptoms in patients can present in a broad range. Mild symptoms may manifest as peripheral tingling or numbness, while severe symptoms may present as severe motor disabilities or sudden blindness. A number of disease modifying therapies are available to help improve quality of life, but there is presently no cure available. Per the current numbers, there are nearly 1 million adults in the US who suffer from MS. Proinflammatory T helper (Th) cells that infiltrate the central nervous system (CNS) are thought to be the initial mediators of disease. Findings from the mouse model of MS, experimental autoimmune encephalomyelitis (EAE) lead to the understanding that MS is an autoimmune disease where T cells are reactive to myelin antigens. Controlling the biology of these T cell responses could bring therapeutic benefits to patients. Previous work from our lab has helped establish the role of the type II arginine methyltransferase, PRMT5 (protein arginine methyltransferase 5) in Th cell expansion and EAE autoimmunity using selective inhibitors. However, the role and mechanism by which PRMT5 modulates T cell responses and EAE progression haven’t been determined. During my time in the lab, we developed two conditional knockout mouse models to evaluate PRMT5’s function in T cells. In my thesis work I used our mouse models, exploratory RNA sequencing (RNA-Seq) and mass spectrometry techniques to uncover the mechanisms of action that drive T cell differentiation, expansion and the PRMT5 mediated symmetric dimethylation (SDM) targets of T cells. We identified a link between PRMT5 and cholesterol metabolism in Th17 cell development. We found that cholesterol pathway intermediates act as agonists for ROR-γt, the signature transcription factor encoding Th17 cells. PRMT5 expression was necessary for proper activity of the enzymes driving cholesterol biosynthesis and the biosynthetic pathway was being controlled by PRMT5 mediated SDM of the transcription factor SREBP1. Additionally, we showed the effects of genetic PRMT5 loss on T cell receptor (TCR) mediated alternative splicing (AS). We found that PRMT5 is responsible for almost 16% of the T cell activation-induced AS. Within the AS list of targets, we identified a novel link between the alternatively spliced calcium-responsive sodium channel Trpm4 and T cell proliferation. We provide evidence for the role of PRMT5 on calcium signaling, NFAT nuclear localization and subsequent IL-2 production and T cell proliferation. Finally, from our list of mass spectrometry targets, we discovered splicing proteins to be direct SDM targets of PRMT5 in T cells. We show that loss of PRMT5 leads to significantly less methylation of SM proteins, SNRPA1 and HNRNPK. Overall, these data provide information on the role of PRMT5 in T cell functions and how their biology could be employed to develop better therapeutics for patients with MS and other T cell mediated autoimmune diseases.
Mireia Guerau-de-Arellano (Advisor)
Stephen Kolb (Committee Member)
Federica Accornero (Committee Member)
Robert Baiocchi (Committee Member)
221 p.
Biomedical Research; Immunology
PRMT5; Cholesterol metabolism; Th17 differentiation; Alternative splicing; MAJIQ; Trpm4; T cell proliferation; Splicing proteins; RNA sequencing; Mass spectrometry; conditional CD4 T cell knockout mouse model;

Recommended Citations

Citations

  • Sengupta, S. (2021). Role of Protein Arginine Methyltransferase 5 in T cell metabolism and alternative splicing [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1638440840794086

    APA Style (7th edition)

  • Sengupta, Shouvonik. Role of Protein Arginine Methyltransferase 5 in T cell metabolism and alternative splicing. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1638440840794086.

    MLA Style (8th edition)

  • Sengupta, Shouvonik. "Role of Protein Arginine Methyltransferase 5 in T cell metabolism and alternative splicing." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1638440840794086

    Chicago Manual of Style (17th edition)

osu1638440840794086
168
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This open access ETD is published by The Ohio State University and OhioLINK.