SETD3 protein is the actin-specific histidine N-methyltransferase

Sebastian Kwiatkowski; Agnieszka K Seliga; Didier Vertommen; Marianna Terreri; Takao Ishikawa; Iwona Grabowska; Marcel Tiebe; Aurelio A Teleman; Adam K Jagielski; Maria Veiga-da-Cunha; Jakub Drozak

doi:10.7554/eLife.37921

SETD3 protein is the actin-specific histidine N-methyltransferase

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

Authors

Affiliations

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.

Abstract

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 2.1.1.85; 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

Substances

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

Grants and funding

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