SETD3 protein is the actin-specific histidine N-methyltransferase

Elife. 2018 Dec 11;7:e37921. doi: 10.7554/eLife.37921.


Protein histidine methylation is a rare post-translational modification of unknown biochemical importance. In vertebrates, only a few methylhistidine-containing proteins have been reported, including β-actin as an essential example. The evolutionary conserved methylation of β-actin H73 is catalyzed by an as yet unknown histidine N-methyltransferase. We report here that the protein SETD3 is the actin-specific histidine N-methyltransferase. In vitro, recombinant rat and human SETD3 methylated β-actin at H73. Knocking-out SETD3 in both human HAP1 cells and in Drosophila melanogaster resulted in the absence of methylation at β-actin H73 in vivo, whereas β-actin from wildtype cells or flies was > 90% methylated. As a consequence, we show that Setd3-deficient HAP1 cells have less cellular F-actin and an increased glycolytic phenotype. In conclusion, by identifying SETD3 as the actin-specific histidine N-methyltransferase, our work pioneers new research into the possible role of this modification in health and disease and questions the substrate specificity of SET-domain-containing enzymes.

Keywords: D. melanogaster; EC; SETD3 protein; actin; actin-specific histidine N-methyltransferase; biochemistry; chemical biology; human; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Conserved Sequence
  • Drosophila melanogaster / classification
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / genetics
  • Fibroblasts / cytology
  • Fibroblasts / enzymology*
  • Glycolysis / genetics
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / pharmacology
  • Humans
  • Kinetics
  • Methylation
  • Models, Molecular
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / enzymology*
  • Phenotype
  • Phylogeny
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Processing, Post-Translational*
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • Actins
  • Recombinant Proteins
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETD3 protein, human

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.