Role of PRMT5 in Cholesterol Metabolism and Th17 Pathogenicity

Abstract Protein Arginine Methyltransferase (PRMT) 5 is an enzyme catalyzing symmetric dimethylation (SDM) of arginine. This post-translational modification is known to be involved in oncogenesis and embryonic development. Our previous work has shown that PRMT5 is induced during T cell activation. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. To study the impact of PRMT5 on gene expression programs induced in activated T cells, we developed a conditional PRMT5 knockout (KO) mouse model in which PRMT5 deletion can be induced in CD4+ T cells after thymic development and performed RNA sequencing (RNAseq) analyses in 3-day activated naïve CD4 T cells. We found that PRMT5 promoted expression of cholesterol biosynthetic pathway enzymes that produce Retinoid-Related Orphan Receptor (ROR) agonists that activate ROR-gt and promote Th17 differentiation. Indeed, Th17 differentiation was blunted in PRMT5 KO T cells. Finally, we identify the cholesterol biosynthesis pathway regulator SREBP-1 as a target of PRMT5 SDM. This work shows that PRMT5 expression in activated T cells is needed for the cholesterol biosynthesis gene expression program, generating ROR-gt agonistic activity and promoting Th17 differentiation. These results point to T cell PRMT5 and the downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17 cell-based diseases.