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

Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4326-31. doi: 10.1073/pnas.1522372113. Epub 2016 Apr 5.

Abstract

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

Keywords: NF-κB; TNFα; arginine methylation; genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / genetics
  • Arginine / metabolism
  • Cell Line
  • Humans
  • Methylation
  • Mice
  • Mice, Knockout
  • Molecular Dynamics Simulation
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • RELA protein, human
  • Rela protein, mouse
  • Repressor Proteins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Nfkb1 protein, mouse
  • N,N-dimethylarginine
  • Arginine
  • PRMT1 protein, human
  • Prmt1 protein, mouse
  • Protein-Arginine N-Methyltransferases