Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan;
Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, Hirakata, Osaka 573-0101, Japan.
Genes Dev. 2023 Aug 1;37(15-16):724-742. doi: 10.1101/gad.350755.123. Epub 2023 Aug 23.
Histidine (His) residues are methylated in various proteins, but their roles and regulation mechanisms remain unknown. Here, we show that carnosine N-methyltransferase 1 (CARNMT1), a known His methyltransferase of dipeptide carnosine (βAla-His), is a major His N1-position-specific methyltransferase. We found that 52 His sites in 20 proteins underwent CARNMT1-mediated methylation. The consensus methylation site for CARNMT1 was identified as Cx(F/Y)xH, a C3H zinc finger (C3H ZF) motif. CARNMT1-deficient and catalytically inactive mutant mice showed embryonic lethality. Among the CARNMT1 target C3H ZF proteins, RNA degradation mediated by Roquin and tristetraprolin (TTP) was affected by CARNMT1 and its enzymatic activity. Furthermore, the recognition of the 3' splice site of the CARNMT1 target C3H ZF protein U2AF1 was perturbed, and pre-mRNA alternative splicing (AS) was affected by CARNMT1 deficiency. These findings indicate that CARNMT1-mediated protein His methylation, which is essential for embryogenesis, plays roles in diverse aspects of RNA metabolism by targeting C3H ZF-type RNA-binding proteins and modulating their functions, including pre-mRNA AS and mRNA degradation regulation.
组氨酸残基在各种蛋白质中被甲基化，但它们的作用和调节机制仍不清楚。在这里，我们表明，肉碱 N-甲基转移酶 1（CARNMT1），一种已知的二肽肉碱（βAla-His）的 His 甲基转移酶，是主要的 His N1-特异性甲基转移酶。我们发现 20 种蛋白质中的 52 个 His 位点发生了 CARNMT1 介导的甲基化。CARNMT1 的保守甲基化位点被鉴定为 Cx(F/Y)xH，这是一个 C3H 锌指（C3H ZF）基序。CARNMT1 缺陷和催化失活突变体小鼠表现出胚胎致死性。在 CARNMT1 的靶标 C3H ZF 蛋白中，Roquin 和 tristetraprolin（TTP）介导的 RNA 降解受到 CARNMT1 和其酶活性的影响。此外，CARNMT1 靶标 C3H ZF 蛋白 U2AF1 的 3'剪接位点识别受到干扰，并且前体 mRNA 可变剪接（AS）受到 CARNMT1 缺陷的影响。这些发现表明，CARNMT1 介导的蛋白质 His 甲基化对于胚胎发生至关重要，通过靶向 C3H ZF 型 RNA 结合蛋白并调节其功能，包括前体 mRNA AS 和 mRNA 降解调节，在 RNA 代谢的多个方面发挥作用。
