SETD3 protein is the actin-specific histidine N-methyltransferase
- Elife. 2018 Dec 11;7:e37921. doi: 10.7554/eLife.37921.
- 1. Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland.
- 2. Protein Phosphorylation Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
- 3. Department of Molecular Biology, Faculty of Biology, University of Warsaw, Warsaw, Poland.
- 4. Department of Cytology, Faculty of Biology, University of Warsaw, Warsaw, Poland.
- 5. German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 6. Heidelberg University, Heidelberg, Germany.
- 7. Metabolic Research Unit, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
- # Contributed equally.
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.