Kwiatkowski, S., Seliga, A.K., Vertommen, D., Terreri, M., Ishikawa, T., Grabowska, I., Tiebe, M., Teleman, A.A., Jagielski, A.K., Veiga-da-Cunha, M., Drozak, J. (2018). SETD3 protein is the actin-specific histidine N-methyltransferase.  eLife 7(): e37921.

FBrf0240976

Research paper

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.

PMC6289574 (PMC) (EuropePMC)