Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Nuclear factor kappa B (NF-kappa B) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-kappa B-activating pathways, the specific repression of NF-kappa B is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNF alpha-induced activation of NF-kappa B. PRMT1 forms a cellular complex with NF-kappa B through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-kappa B target genes in response to TNF alpha. Molecular dynamics simulations of the DNA-bound RelA: p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA-NF-kappa B complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNF alpha/NF-kappa B signaling.