2. Academic Validation
  3. siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9

siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9

  • J Biol Chem. 2021 Nov;297(5):101230. doi: 10.1016/j.jbc.2021.101230.
Hiroaki Daitoku 1,  Momoka Someya 2,  Koichiro Kako 3,  Takahiro Hayashi 4,  Tatsuya Tajima 5,  Hikari Haruki 2,  Naoki Sekiguchi 6,  Toru Uetake 2,  Yuto Akimoto 6,  Akiyoshi Fukamizu 7
Affiliations

Affiliations

  • 1 Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: hiroakid@tara.tsukuba.ac.jp.
  • 2 Master's Program in Agro-Bioresources Science and Technology, Degree Programs in Life and Earth Sciences, Graduate School of Sciences and Technology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 3 Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 4 Doctoral Program in Life and Agricultural Sciences, Degree Programs in Life and Earth Sciences, Graduate School of Sciences and Technology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 5 Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 6 College of Agro-Biological Resource Sciences, School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 7 Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan; The World Premier International Research Center Initiative (WPI), International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan. Electronic address: akif@tara.tsukuba.ac.jp.
PMID: 34562450 DOI: 10.1016/j.jbc.2021.101230
Abstract

Protein methylation is one of the most common post-translational modifications observed in basic amino acid residues, including lysine, arginine, and histidine. Histidine methylation occurs on the distal or proximal nitrogen atom of its imidazole ring, producing two isomers: Nτ-methylhistidine or Nπ-methylhistidine. However, the biological significance of protein histidine methylation remains largely unclear owing in part to the very limited knowledge about its contributing Enzymes. Here, we identified mammalian seven-β-strand methyltransferase METTL9 as a histidine Nπ-methyltransferase by siRNA screening coupled with methylhistidine analysis using LC-tandem MS. We demonstrated that METTL9 catalyzes Nπ-methylhistidine formation in the proinflammatory protein S100A9, but not that of Myosin light chain kinase MYLK2, in vivo and in vitro. METTL9 does not affect the heterodimer formation of S100A9 and S100A8, although Nπ-methylation of S100A9 at His-107 overlaps with a zinc-binding site, attenuating its affinity for zinc. Given that S100A9 exerts an antimicrobial activity, probably by chelation of zinc essential for the growth of bacteria and fungi, METTL9-mediated S100A9 methylation might be involved in the innate immune response to Bacterial and fungal Infection. Thus, our findings suggest a functional consequence for protein histidine Nπ-methylation and may add a new layer of complexity to the regulatory mechanisms of post-translational methylation.

Keywords

METTL9; S100A9; histidine methylation; zinc binding.

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