PRMT5 Controls Pathogenicity and Metabolic Genes During Th17 Polarization

Abstract PRMT5 catalyzes symmetric dimethylation (SDM) on arginine residues. PRMT5 methylates histone H3 and H4 producing remodeling of chromatin and regulation of gene transcription. PRMT5 is induced after T cell activation. Furthermore, both PRMT5 inhibitors and PRMT5 knockdown impair T cell proliferation and activation. However, the role of PRMT5 in T cell differentiation has not been analyzed. T cells undergo metabolic reprograming during activation which is critical for polarization. Differentiating T cells increase bioenergetics and anabolic pathways enhancing glycolysis, catabolism, uptake of fatty acids and oxidative phosphorylation. Whether PRMT5 has an impact on Th17 differentiation and metabolic reprograming is unknown. To address this question, we performed Th17 differentiation and RNA sequencing analyses in T cells from PRMT5fl/fl and iCD4-PRMT5Δ/Δ mice. Th17 differentiation was sharply suppressed in PRMT5 KO T cells, in which 25–30% of genes in the glycolysis, lactate or TCA pathways were reduced. To evaluate the functional effects of PRMT5 on energy metabolism, extracellular acidification rate (ECAR) and Oxygen consumption rate (OCR) were analyzed in Jurkat T cells transduced with control or PRMT5 shRNA and lactate secretion was measured on supernatants of Th1 and Th17 cells from PRMT5fl/fl and iCD4-PRMT5Δ/Δ mice. Knock down of PRMT5 decreased ECAR in Jurkat cells and lactate production in Th1 and Th17 cells in absence of PRMT5. In conclusion, PRMT5 promotes glycolytic energy metabolism and Th17 differentiation in T cells.