复旦大学蓝斐等研究人员合作发现，SMYD5是一种核糖体甲基转移酶可催化RPL40赖氨酸的甲基化，来增强翻译输出并促进肝细胞癌的发生。这一研究成果于2024年8月5日在线发表在国际学术期刊《细胞研究》上。

研究人员发现，SMYD5对RPL40第22位赖氨酸（K22）具有强大的体外催化活性，并主要在细胞内催化RPL40第22位赖氨酸的三甲基化（K22me3）。SMYD5和RPL40 K22me3的缺失会导致翻译输出减少和延伸过程的紊乱，表现为核糖体碰撞的增加。SMYD5和RPL40 K22me3在肝细胞癌（HCC）中上调，并与患者预后负相关。缺乏SMYD5使HCC细胞在二维和三维培养中对mTOR抑制剂过度敏感。

此外，在遗传工程小鼠模型和患者衍生异种移植（PDX）模型中，SMYD5的缺失显著抑制HCC的发展和生长，而在PDX模型中，该抑制作用在mTOR抑制的同时进一步增强。该研究揭示了SMYD5和RPL40 K22me3轴在翻译延伸中的新角色，并强调了在HCC中靶向SMYD5的治疗潜力，特别是与mTOR抑制的联合应用。这项工作还从概念上拓宽了赖氨酸甲基化的理解，将其重要性从转录调控扩展到翻译控制。

据了解，赖氨酸甲基化通常被认为调节基因转录，但其在翻译中的作用尚未被深入研究。RPL40上的K22me3早在27年前首次被报道，该蛋白是位于GTP酶激活中心的核心核糖体蛋白。然而，其甲基转移酶和在翻译中的作用仍未被探索。

附：英文原文

Title: SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma

Author: Miao, Bisi, Ge, Ling, He, Chenxi, Wang, Xinghao, Wu, Jibo, Li, Xiang, Chen, Kun, Wan, Jinkai, Xing, Shenghui, Ren, Lingnan, Shi, Zhennan, Liu, Shengnan, Hu, Yajun, Chen, Jiajia, Yu, Yanyan, Feng, Lijian, Flores, Natasha M., Liang, Zhihui, Xu, Xinyi, Wang, Ruoxin, Zhou, Jian, Fan, Jia, Xiang, Bin, Li, En, Mao, Yuanhui, Cheng, Jingdong, Zhao, Kehao, Mazur, Pawel K., Cai, Jiabin, Lan, Fei

Issue&Volume: 2024-08-05

Abstract: While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

DOI: 10.1038/s41422-024-01013-3

Source: https://www.nature.com/articles/s41422-024-01013-3