AbstractWhile 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.

摘要尽管赖氨酸甲基化以转录调控基因表达而闻名，但其在翻译中的意义在很大程度上尚不清楚。。

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.

然而，它的甲基转移酶和在翻译中的作用仍未被探索。在这里，我们报道SMYD5对RPL40 K22具有强大的体外活性，并主要催化细胞中的RPL40 K22me3。SMYD5和RPL40 K22me3的丢失导致翻译输出减少和延伸受到干扰，核糖体碰撞增加证明了这一点。

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.

SMYD5和RPL40 K22me3在肝细胞癌（HCC）中上调，与患者预后呈负相关。耗尽SMYD5使HCC细胞在2D和3D培养物中对mTOR抑制过敏。此外，SMYD5的缺失显着抑制了基因工程小鼠和患者来源的异种移植（PDX）模型中HCC的发展和生长，同时mTOR抑制进一步增强了PDX模型中的抑制作用。

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..

。这项工作还从概念上拓宽了对赖氨酸甲基化的理解，将其意义从转录调控扩展到翻译控制。。

IntroductionProtein lysine Nε-methylation plays a crucial role in various biological processes. While its impact on transcription regulation via histone proteins has been extensively studied over the past two decades or so, its role in translation remains largely unexplored. In this context, several mammalian ribosomal proteins, such as RPL4, RPL29, RPL40, and RPL36A, have been reported to contain lysine methylation.1,2,3 Among these, RPL40 is a special ribosomal protein encoded by the UBA52 gene.

简介蛋白质赖氨酸Nε-甲基化在各种生物过程中起着至关重要的作用。虽然在过去的二十年左右的时间里，它通过组蛋白对转录调控的影响已经得到了广泛的研究，但它在翻译中的作用仍然很大程度上未被探索。在这种情况下，据报道几种哺乳动物核糖体蛋白，如RPL4，RPL29，RPL40和RPL36A，含有赖氨酸甲基化。其中，RPL40是由UBA52基因编码的特殊核糖体蛋白。

The precursor UBA52 protein is a fusion protein of 128 amino acids (aa), comprising an N-terminal fusion of a ubiquitin module (76 aa). After the removal of ubiquitin, the mature form of RPL40 is 52 aa in length and is one of the last components assembled into the 60S ribosomal subunit in cytoplasm.4,5 In the mature 80S ribosome, RPL40 is located near the P stalk/GTPase Activation Center (GAC) and Sarcin-Ricin Loop (SRL), where elongation factors eEF1A and eEF2 bind.

前体UBA52蛋白是128个氨基酸（aa）的融合蛋白，包含泛素模块（76 aa）的N端融合蛋白。去除泛素后，RPL40的成熟形式长度为52 aa，是细胞质中最后组装成60S核糖体亚基的成分之一。4,5在成熟的80S核糖体中，RPL40位于P茎/GTPase激活中心（GAC）和Sarcin-Ricin环（SRL）附近，延伸因子eEF1A和eEF2结合。

The elongation factors are crucial for recruiting peptidyl-tRNA to the A-site and for translocating it from A-site to P-site. RPL40 has been proposed to selectively regulate stress-related mRNA translation and confer resistance to elongation inhibitor Sordarin in yeasts,4,6 suggesting an essential function of RPL40 in protein synthesis.

延伸因子对于将肽基tRNA募集到A位点以及将其从A位点转移到P位点至关重要。已经提出RPL40选择性调节应激相关的mRNA翻译，并赋予酵母对延伸抑制剂Sordarin的抗性，4,6表明RPL40在蛋白质合成中的重要功能。

Importantly, the trimethylation of K22 on RPL40 (RPL40 K22me3, equivalent to UBA52 K98me3) was identified by mass spectrometry analysis in rat liver 27 years ago,1 and visualized in recent high-resolution ribosome structural studies.2,3 However, the role of this modification in translation and ribosome function remains unclear.SET and MYND domain-containing (SMYD) proteins constitute an evolutionarily conserved subfamily of lysine methyltransferases, characterized by a catalytic SE.

重要的是，27年前，通过质谱分析在大鼠肝脏中鉴定了RPL40（RPL40 K22me3，相当于UBA52 K98me3）上K22的三甲基化，1并在最近的高分辨率核糖体结构研究中可视化[2,3]。然而，这种修饰在翻译和核糖体功能中的作用仍不清楚。SET和含有MYND结构域的（SMYD）蛋白构成赖氨酸甲基转移酶的进化保守亚家族，其特征在于催化SE。

Data availability

数据可用性

High-throughput sequencing data were deposited to the Gene Expression Omnibus with an accession number GSE241588.

高通量测序数据以登录号GSE241588保存到Gene Expression Omnibus。

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Download referencesAcknowledgementsWe thank the Core Facility of Shanghai Medical College, Fudan University for providing instrumental help. This work is supported in part by grants from the National Natural Science Foundation of China (31925010 to F.L., 82272703 to J. Cai, 32300461 to C.H.), the National Key R&D Program of China (2021YFA1300100 to F.L.), the Elite Youth Project of Natural Science Foundation of Fujian Province (2023J06056 to J. Cai) and the China National Postdoctoral Program for Innovative Talents (BX20230098 to C.H.).Author informationAuthor notesThese authors contributed equally: Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu.Authors and AffiliationsShanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, ChinaBisi Miao, Ling Ge, Chenxi He, Kun Chen, Jinkai Wan, Shenghui Xing, Lingnan Ren, Zhennan Shi, Yajun Hu, Jiajia Chen, Zhihui Liang, Xinyi Xu, Ruoxin Wang, Jian Zhou, Jia Fan, Jiabin Cai & Fei LanChina Novartis Institutes for BioMedical Research, Shanghai, ChinaXinghao Wang, Shengnan Liu, Yanyan Yu, Lijian Feng, Bin Xiang, En Li & Kehao ZhaoDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USAJibo Wu, Natasha M.

下载参考文献致谢我们感谢复旦大学上海医学院核心设施提供的仪器帮助。这项工作部分得到了国家自然科学基金（31925010授予F.L.，82272703授予J.Cai，32300461授予C.H.），国家重点研发计划（2021YFA1300100授予F.L.），福建省自然科学基金精英青年项目（2023J06056授予J.Cai）和中国国家创新人才博士后计划（BX20230098授予C.H.）的资助。作者信息作者注意到这些作者做出了同样的贡献：Bisi Miao，Ling Ge，Chenxi He，Xinghao Wang，Jibo Wu。作者和所属单位上海医学表观遗传学重点实验室，科学技术部医学表观遗传学与代谢国际合作实验室，生物医学科学研究所，教育部致癌与癌症侵袭重点实验室，复旦大学中山医院肝癌研究所，上海，中国毕斯苗，凌格，陈希河，陈坤，金开万，邢生辉，任岭南，石振南，胡亚军，陈佳佳，梁志辉，徐欣怡，王若新，周健，贾凡，蔡嘉斌和费兰华诺华生物医学研究所，上海，王兴浩，刘盛南，严燕于，李建峰，向斌，李恩和赵克浩德克萨斯大学MD安德森癌症中心实验放射肿瘤学系，德克萨斯州休斯顿，乌萨吉博·吴，娜塔莎·M。

Flores & Pawel K. MazurMinhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, ChinaXiang Li & Jingdong ChengDepartment of Neurology of The Seco.

Flores＆Pawel K.MazurMinhang医院和生物医学研究所，上海医学表观遗传学重点实验室，医学表观遗传学与代谢国际合作实验室，复旦大学，上海，中国李翔和程景东Seco神经病学系。

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PubMed Google ScholarContributionsB.M., L.G., C.H., X.W., and J. Wu contributed equally to the study. They were responsible for the experimental design, conduction, data process, and manuscript preparation. B.M., X.W., C.H., K.C., J. Wan, S.L., L.R., Z.L., and L.F. identified enzymatic activity and completed biochemistry assays, as well as cellular characterization under the guidance from F.L.

PubMed谷歌学术贡献b。M、 ，L.G.，C.H.，X.W。和J.Wu对这项研究做出了同样的贡献。他们负责实验设计，传导，数据处理和手稿准备。B、 M.，X.W.，C.H.，K.C.，J.Wan，S.L.，L.R.，Z.L。和L.F.在F.L.的指导下鉴定了酶活性并完成了生物化学测定以及细胞表征。

K.Z., B.X., E.L., L.R., C.H., Y.H., J. Chen, Y.Y., and K.C. performed MS analyses to identify methylation site and trimethylation abundance. L.G., C.H., and S.X. conducted drug library screen and most cancer cell growth analyses. Z.S. generated the HEK293T RPL40 K22R KI cell line. L.G. and C.H. performed the rescue experiment with the assistance of X.X.

K、 Z.，B.X.，E.L.，L.R.，C.H.，Y.H.，J.Chen，Y.Y。和K.C.进行了MS分析，以鉴定甲基化位点和三甲基化丰度。五十、 G.，C.H。和S.X.进行了药物库筛选和大多数癌细胞生长分析。Z、 S.产生了HEK293T RPL40 K22R KI细胞系。五十、 G.和C.H.在X.X的帮助下进行了救援实验。

L.G. and Z.L. verified the hypersensitivity to translation inhibitors targeting A-site in cells. Z.L. and R.W. provided help for manuscript preparation. L.G. and C.H. performed polysome profiling and ribo-seq with the help of Y.M. and J. Cheng. X.L. and C.H. analyzed ribo-seq data and J. Cheng analyzed the structure.

五十、 G.和Z.L.证实了对靶向细胞中A位点的翻译抑制剂的超敏性。Z、 L.和R.W.为稿件准备提供了帮助。五十、 G.和C.H.在Y.M.和J.Cheng的帮助下进行了多核糖体分析和ribo-seq。十、 L.和C.H.分析了ribo-seq数据，J.Cheng分析了结构。

J. Cai conducted patient cancer sample IHC analyses under the guidance from J.Z. and J.F. J. Wu and N.M.F. were responsible for mouse work of SNU449 and HCC models under the guidance from P.K.M. P.K.M., J. Cai, and F.L. were equally responsible for project overseeing and planning, data interpretation, and manuscript preparation.Corresponding authorsCorrespondence to.

J、 Cai在J.Z.和J.F.J.的指导下进行了患者癌症样本IHC分析。Wu和N.M.F.在P.K.M.P.K.M.的指导下负责SNU449和HCC模型的小鼠工作，J.Cai和F.L.同样负责项目监督和规划，数据解释和手稿准备。通讯作者通讯。

Pawel K. Mazur, Jiabin Cai or Fei Lan.Ethics declarations

Pawel K.Mazur，蔡家斌或费兰。道德宣言

Competing interests

相互竞争的利益

Fei Lan is a scientific co-founder and stockholder of Active Motif Shanghai, Inc. and Alternative Bio, Inc. Pawel K. Mazur is a scientific co-founder, consultant, and stockholder of Amplified Medicines, Inc. and Ikena Oncology, Inc., and a consultant and stockholder of Alternethiative bio, Inc.

费兰是Active Motif Shanghai，Inc.和Alternative Bio，Inc.的科学联合创始人和股东。Pawel K.Mazur是Amplified Medicines，Inc.和Ikena Oncology，Inc.的科学联合创始人、顾问和股东，也是Alternethiative Bio，Inc.的顾问和股东。

Supplementary informationSupplementary information, Fig S1Supplementary information, Fig S2Supplementary information, Fig S3Supplementary information, Fig S4Supplementary information, Fig S5Supplementary information, Fig S6Supplementary information, Fig S7Supplementary information, Fig S8Supplementary information, Figure LegendsSupplementary information, Table S1Supplementary information, Table S2Supplementary information, Table S3Supplementary information, Table S4Rights and permissions.

补充信息补充信息，图S1补充信息，图S2补充信息，图S3补充信息，图S4补充信息，图S5补充信息，图S6补充信息，图S7补充信息，图S8补充信息，图传说补充信息，表S1补充信息，表S2补充信息，表S3补充信息，表S4权利和权限。

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Reprints and permissionsAbout this articleCite this articleMiao, B., Ge, L., He, C. et al. SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma.

转载和许可本文引用本文Miao，B.，Ge，L.，He，C。等人。SMYD5是一种核糖体甲基转移酶，可催化RPL40赖氨酸甲基化以增强翻译输出并促进肝细胞癌。

Cell Res (2024). https://doi.org/10.1038/s41422-024-01013-3Download citationReceived: 19 June 2024Accepted: 23 July 2024Published: 05 August 2024DOI: https://doi.org/10.1038/s41422-024-01013-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Cell Res（2024）。https://doi.org/10.1038/s41422-024-01013-3Download引文接收日期：2024年6月19日接受日期：2024年7月23日发布日期：2024年8月5日OI：https://doi.org/10.1038/s41422-024-01013-3Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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