NF-kB/mTOR/MYC axis drives PRMT5 protein induction after T cell activation

Abstract

Abstract Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells. Clinical data has provided evidence that MS patient T cells display an activated or memory phenotype and genome-wide association studies (GWAS) have identified single nucleotide polymorphisms linked to NF-kB complex and MYC genes in MS patients. These data imply a role for TcR (T cell receptor) signaling pathways in MS. PRMT5 is the major type II arginine methyltransferase catalyzing the symmetric dimethylation of histones and other proteins. Our lab has recently reported PRMT5 plays a crucial role in inflammatory T cell expansion and EAE disease. From cancer studies, we are aware of links between NF-kB/MYC signaling and PRMT5 induction. Here, we unravel the impact of NF-kB/MYC pathways in T cell PRMT5 expression and pathogenic T cell responses. We used naïve and memory mouse Th1/Th2 CD4+T cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Naïve (initial) mouse T cell activation resulted in NF-kB-dependent transient Prmt5 transcription and NF-kB, mTOR and Myc-dependent PRMT5 protein induction. Recall activation in memory T cells showed rapid induction of PRMT5 protein expression, supported by both transcription and loss of Prmt5-targeting miRNAs. These results highlight the importance of the NF-kB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS.