PT - JOURNAL ARTICLE AU - Eriko Matsuura-Suzuki AU - Tadahiro Shimazu AU - Mari Takahashi AU - Kaoru Kotoshiba AU - Takehiro Suzuki AU - Kazuhiro Kashiwagi AU - Yoshihiro Sohtome AU - Mai Akakabe AU - Mikiko Sodeoka AU - Naoshi Dohmae AU - Takuhiro Ito AU - Yoichi Shinkai AU - Shintaro Iwasaki TI - METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance AID - 10.1101/2021.07.29.454307 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.07.29.454307 4099 - http://biorxiv.org/content/early/2021/07/29/2021.07.29.454307.short 4100 - http://biorxiv.org/content/early/2021/07/29/2021.07.29.454307.full AB - Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a substrate for the modification. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traverse on tyrosine codons, allowing the proper folding of synthesized proteins. By performing an in vitro methylation assay with a methyl donor analog and quantitative mass spectrometry, we found that His245 of RPL3 is methylated at the τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed stoichiometric modification and suggested a role in translation tuning. Indeed, genome-wide ribosome profiling revealed suppressed ribosomal translocation at tyrosine codons by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from the cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of a “ribosome code” that ensures proteome integrity in cells.Competing Interest StatementThe authors have declared no competing interest.