Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNF?/NF-?B response.

ABSTRACT: Nuclear factor kappa B (NF-?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-?B-activating pathways, the specific repression of NF-?B is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNF?-induced activation of NF-?B. PRMT1 forms a cellular complex with NF-?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-?B target genes in response to TNF?. 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-?B complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNF?/NF-?B signaling.

SUBMITTER: Reintjes A 

PROVIDER: S-EPMC4843428 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature