METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance
METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance
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METTL18介导的RPL3组氨酸甲基化调节翻译延伸以维持蛋白质稳态
DOI：
10.1101/2021.07.29.454307
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Iwasaki Shintaro
中科院分区：
文献类型：
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作者：
Matsuura-Suzuki Eriko;Shimazu Tadahiro;Takahashi Mari;Kotoshiba Kaoru;Suzuki Takehiro;Kashiwagi Kazuhiro;Sohtome Yoshihiro;Akakabe Mai;Sodeoka Mikiko;Dohmae Naoshi;Ito Takuhiro;Shinkai Yoichi;Iwasaki Shintaro
蛋白质甲基化主要发生在赖氨酸和精氨酸残基上，但组氨酸也作为甲基化底物。然而，据报道，负责这种修饰的酶数量有限。此外，组氨酸甲基化的生物学作用迄今仍知之甚少。在这里，我们报告了人的METTL18是核糖体蛋白RPL3的组氨酸甲基转移酶，这种修饰特异性地减缓了核糖体在Tyr密码子上的穿越，允许合成蛋白的适当折叠。通过与甲基供体类似物进行体外甲基化实验和定量质谱分析，我们发现RPL3的His245在τ-N位置被MetTL18甲基化。经过修饰和未修饰的核糖体的结构比较显示出化学计量比的改变，并表明在翻译反应中发挥了作用。事实上，全基因组核糖体图谱和体外翻译实验表明，酪氨酸密码子的翻译延伸受到RPL3甲基化的抑制。由于较慢的伸长为新生的蛋白质折叠提供了足够的时间，RPL3甲基化保护细胞免受富含Tyr的蛋白质的细胞聚集。我们的结果显示，组氨酸甲基化是核糖体修饰的一个例子，它确保了细胞中蛋白质组的完整性。
Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a methylation substrate. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood to date. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traversal on Tyr 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 reactions. Indeed, genome-wide ribosome profiling and an in vitro translation assay revealed that translation elongation at Tyr codons was suppressed 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 modification that ensures proteome integrity in cells.