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

SETD3 protein is the actin-specific histidine N-methyltransferase.

Author information

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

PMID:
30526847
PMCID:
PMC6289574
DOI:
10.7554/eLife.37921
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

SK, AS, DV, MT, TI, IG, MT, AT, AJ, MV, JD No competing interests declared

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