更新于：2024-11-01

METTL14

更新于：2024-11-01

基本信息

别名

hMETTL14、KIAA1627、methyltransferase 14, N6-adenosine-methyltransferase subunit

+ [3]

简介

The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis (PubMed:24316715, PubMed:24407421, PubMed:25719671, PubMed:29348140, PubMed:27373337, PubMed:27281194). In the heterodimer formed with METTL3, METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core (PubMed:27627798, PubMed:27373337, PubMed:27281194, PubMed:29348140). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability and processing (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A acts as a key regulator of mRNA stability by promoting mRNA destabilization and degradation (By similarity). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity).

关联

项与 METTL14 相关的药物

WD6305

靶点

METTL14 x METTL3

作用机制

METTL14 降解剂 [+1]

在研机构

中国科学院上海药物研究所

原研机构

中国科学院上海药物研究所

在研适应症

急性髓性白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

METTL3/14 modulators(Canthera Discovery)

靶点

METTL14 x METTL3

作用机制

METTL14 modulators [+1]

在研机构

Canthera Discovery Ltd

原研机构

Canthera Discovery Ltd

在研适应症

急性髓性白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 METTL14 相关的临床结果

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100 项与 METTL14 相关的转化医学

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0 项与 METTL14 相关的专利（医药）

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788

项与 METTL14 相关的文献（医药）

2025-06-01·Neural Regeneration Research

Enhancing m6A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Article

作者: Qin, Tian ; Lu, Hongbin ; Cao, Yong ; Qin, Yiming ; Hu, Jianzhong ; Li, Chengjun ; Jin, Yuxin ; Yuan, Feifei

JOURNAL/nrgr/04.03/01300535-202506000-00026/figure1/v/2024-08-08T040853Z/r/image-tiff Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine (m6A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m6A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m6A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m6A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m6A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

2024-12-31·Cancer Biology & Therapy

M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells

Article

作者: Wang, Yu-Yan ; Dai, Ning ; Zhang, Xin ; Gao, Wei-Ran ; Zhao, An-Qi ; Yin, Yu ; Ye, Lian-Hua

DIRAS family GTPase 1 (DIRAS1) has been reported as a potential tumor suppressor in other human cancer. However, its expression pattern and role in cervical cancer remain unknown. Knockdown of DIRAS1 significantly promoted the proliferation, growth, migration, and invasion of C33A and SiHa cells cultured in vitro. Overexpression of DIRAS1 significantly inhibited the viability and motility of C33A and SiHa cells. Compared with normal cervical tissues, DIRAS1 mRNA levels were significantly lower in cervical cancer tissues. DIRAS1 protein expression was also significantly reduced in cervical cancer tissues compared with para-cancerous tissues. In addition, DIRAS1 expression level in tumor tissues was significantly negatively correlated with the pathological grades of cervical cancer patients. DNA methylation inhibitor (5-Azacytidine) and histone deacetylation inhibitor (SAHA) resulted in a significant increase in DIRAS1 mRNA levels in C33A and SiHa cells, but did not affect DIRAS1 protein levels. FTO inhibitor (FB23-2) significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels. Moreover, the down-regulation of METTL3 and METTL14 expression significantly inhibited DIRAS1 protein expression, whereas the down-regulation of FTO and ALKBH5 expression significantly increased DIRAS1 protein expression. In conclusion, DIRAS1 exerts a significant anti-oncogenic function and its expression is significantly downregulated in cervical cancer cells. The m6A modification may be a key mechanism to regulate DIRAS1 mRNA stability and protein translation efficiency in cervical cancer.

2024-12-31·Cancer Biology & Therapy

METTL14 decreases FTH1 mRNA stability via m6A methylation to promote sorafenib-induced ferroptosis of cervical cancer

Article

作者: He, Sili ; Li, Lijie ; Wang, Chen ; Zeng, Jie ; Yang, Yanfei

Cervical cancer (CC) is a prevalent malignancy among women worldwide. This study was designed to investigate the role of METTL14 in sorafenib-induced ferroptosis in CC. METTL14 expression and m6A methylation were determined in CC tissues, followed by analyzes correlating these factors with clinical features. Subsequently, METTL14 was knocked down in CC cell lines, and the effects on cell proliferation, mitochondrial morphology and ferroptosis were assessed using CCK-8, microscopy, and markers associated with ferroptosis, respectively. The regulatory relationship between METTL14 and FTH1 was verified using qRT-PCR and luciferase reporter assays. The functional significance of this interaction was further investigated both in vitro and in vivo by co-transfecting cells with overexpression vectors or shRNAs targeting METTL14 and FTH1 after sorafenib treatment. METTL14 expression and m6A methylation were significantly reduced in CC tissues, and lower METTL14 expression levels were associated with a poorer CC patients' prognosis. Notably, METTL14 expression increased during sorafenib-induced ferroptosis, and METTL14 knockdown attenuated the ferroptotic response induced by sorafenib in CC cells. FTH1 was identified as a direct target of METTL14, with METTL14 overexpression leading to increased m6A methylation of FTH1 mRNA, resulting in reduced stability and expression of FTH1 in CC. Furthermore, FTH1 overexpression or treatment with LY294002 partially counteracted the promotion of sorafenib-induced ferroptosis by METTL14. In vivo xenograft experiments demonstrated that inhibiting METTL14 reduced the anticancer effects of sorafenib, whereas suppression of FTH1 significantly enhanced sorafenib-induced ferroptosis and increased its anticancer efficacy. METTL14 reduces FTH1 mRNA stability through m6A methylation, thereby enhancing sorafenib-induced ferroptosis, which contributes to suppressing CC progression via the PI3K/Akt signaling pathway.

项与 METTL14 相关的新闻（医药）

2024-09-30

·生物制品圈

复旦大学束敏峰团队：神经胶质瘤的潜在治疗靶点

【导读】感染单纯疱疹病毒1（HSV-1）后，该病毒会部署多种策略，来逃避宿主的先天免疫反应。然而，控制这种现象的机制仍然难以捉摸。在这项研究中，团队发现HSV-1通过在神经胶质瘤细胞的早期感染期间选择性地减少METTL14蛋白，导致总体m6A水平降低。 2024年9月，复旦大学基础医学院束敏峰团队在期刊《Cell Reports》上发表了题为“HSV-1-induced N6-methyladenosine reprogramming via ICP0-mediated suppression of METTL14 potentiates oncolytic activity in glioma”的研究论文。研究结果确定了ICP0引导的m6A修饰控制抗病毒免疫反应，并表明靶向METTL14/ISG15代表了在神经胶质瘤治疗中增强oHSV-1溶瘤活性的潜在策略。 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01107-0 研究背景 01 N6-甲基腺苷（m6A）RNA 修饰是真核mRNA分子的常见特征，该复合物由METTL3、METTL14、WTAP、VIRMA和RBM15组成。IGF2BP3是一种在胚胎发育过程中高度表达的蛋白质，并且在包括多形性胶质母细胞瘤在内的各种癌症中显著上调。m6A在许多病毒的生命周期和细胞对病毒感染的反应中发挥作用。此外，宿主细胞中的m6A表观转录组在病毒感染后发生改变，导致感染增强或宿主耐药性。溶瘤病毒疗法是一种新兴的癌症治疗方式，它使用复制病毒。溶瘤病毒（OVs）直接引起肿瘤细胞裂解，导致可溶性抗原和危险信号的释放，从而刺激抗肿瘤免疫反应。2015年美国食品和药品监督管理局（FDA）批准的第一个OV是IMLYGIC，一种用于治疗晚期黑色素瘤的转基因溶瘤HSV-1（oHSV-1）。DELYTACT是第三代oHSV-1，在肿瘤细胞中具有更强的复制能力。根据一项有19名入组患者的2期临床试验的结果，其在日本获得了有条件和限期的上市批准，用于治疗恶性神经胶质瘤，这是成人最常见和最致命的原发性脑恶性肿瘤。在这项研究中，团队报道了早期HSV-1感染以ICP0依赖性方式选择性地诱导METTL14降解，导致总体m6A水平降低。METTL14诱导的ISG15表达增强（由IGF2BP3介导）在HSV-1感染期间促进抗病毒作用。敲除METTL14，增强了HSV-1的传播和oHSV-1在神经胶质瘤治疗中的溶瘤活性。图形摘要研究进展 02 METTL14诱导的ISG15表达增强促进HSV-1感染期间的抗病毒作用 METTL14过表达，导致WT HSV-1和oHSV-1的病毒基因表达在mRNA和蛋白水平上受到抑制。METTL14过表达，导致U87MG神经胶质瘤细胞中oHSV-1-EGFP复制减少。相反，使用shRNA敲低METTL14，促进了WT HSV-和oHSV-1复制。这些结果表明，METTL14减轻了HSV-1的复制。 WT METTL14过表达，适度挽救了HSV-1感染介导的ISG15抑制。METTL14突变体（K156R和K162R）不能被ICP0泛素化，显著阻断了HSV-1诱导的ISG15减少。METTL14 的过表达，显著减弱了shMETTL14诱导的病毒基因表达增强。METT14通过上调ISG15的表达，来抑制HSV-1感染。总之，HSV-1通过ICP0/METTL14/ISG15 通路，减弱抗病毒作用。 METTL14诱导的ISG15表达增强，在oHSV-1感染期间促进抗病毒作用 METTL14敲除增强了oHSV-1在胶质瘤异种移植小鼠中的抗肿瘤活性体内研究表明，与阴性对照相比，注射METTL14敲低细胞的小鼠，表现出对肿瘤生长的显著促进。oHSV-1抑制颅内神经胶质瘤生长的能力较低。在oHSV-1治疗后，shMETTL14组的肿瘤几乎消失了。oHSV-1显著抑制METTL14和ISG15表达。METTL14敲低，强烈促进了oHSV-1复制。在正常脑组织中，未检测到病毒基因产物（ICP0）。敲低U87MG细胞中的METTL14，显著增加了oHSV-1的溶瘤活性，其特征是肿瘤大小减小、存活时间延长和病毒基因表达增强。此外，在正常脑组织中未检测到病毒基因产物（ICP0）。这些数据表明，抑制METTL14会增强病毒复制，有助于增加oHSV-1对神经胶质瘤的抗肿瘤作用，并且敲除METTL14不会影响oHSV-1的肿瘤特异性。抑制METTL14显著增强携带GL261衍生的神经胶质瘤异种移植物的小鼠oHSV-1的抗肿瘤活性研究结论 03 研究结果强调了HSV-1编码的E3泛素连接酶ICP0在METTL14降解中的重要性，随后导致通过m6A依赖性途径抑制ISG15表达。这强调了oHSV-1治疗，以低METTL14表达为特征的神经胶质瘤的有效性。此外，特异性METTL14抑制剂的开发，显示出作为潜在增强剂的前景，其在神经胶质瘤治疗中与oHSV-1协同作用。参考资料： 1.Deng, X. ∙ Su, R. ∙ Weng, H. ... RNA N(6)-methyladenosine modification in cancers: current status and perspectives Cell Res. 2018; 28:507-517 2.Huang, H. ∙ Weng, H. ∙ Sun, W. ... Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation Nat. Cell Biol. 2018; 20:285-295 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

信使RNA临床2期

2024-09-10

·生物探索

Cell Metab丨肖玲等揭示棕色脂肪中的m⁶A mRNA甲基化通过独立于UCP1的前列腺素信号调控全身胰岛素敏感性

引言棕色脂肪组织（BAT）因其通过解偶联蛋白1（UCP1）产生热量，成为治疗和预防肥胖及相关代谢疾病的潜在靶点。研究表明，冷刺激激活的BAT可以通过能量消耗减少体脂，改善心脏代谢健康，特别在超重和肥胖个体中效果显著。尽管BAT的产热功能备受关注，近年来越来越多的证据表明，BAT还通过分泌各种有益因子（"BATokine"，如肽类、蛋白质、脂质、miRNA等）对全身代谢产生积极调节。其中，一类被称为“BAT lipokine”的脂质因子尤为重要【1,2】，它与胰岛素敏感性、葡萄糖耐量以及炎症调节密切相关。 m6A（N6-甲基腺嘌呤）是RNA中最常见的内部甲基化修饰之一，广泛存在于真核生物的mRNA和非编码RNA中，在RNA剪接、翻译、稳定性和降解等过程中发挥重要作用。m6A修饰与干细胞分化、肿瘤发生、免疫调控和代谢紊乱等生理与病理过程密切相关。尽管已知m6A在棕色脂肪产热中具有重要作用，但m6A是否通过调控棕色脂肪分泌的"BATokine"影响全身代谢尚不清楚。 2024年9月9日，哈佛医学院及Joslin糖尿病研究中心（Joslin Diabetes Center）的Rohit N. Kulkarni教授团队在Cell Metabolism在线发表了题为m6A mRNA Methylation in Brown Fat Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis Independent of UCP1的研究成果。该研究通过基因组学、甲基化组学和脂质组学等多组学手段，首次揭示了：1. 由甲基转移酶14（METTL14）介导的m6A修饰，通过负向调控BAT中前列腺素合成酶的表达，抑制了前列腺素PGE2和PGF2α的合成；2. 敲除BAT中的METTL14显著提高了PGE2和PGF2α的水平，从而改善了胰岛素敏感性，促进了白色脂肪棕色化，并降低了肥胖小鼠体重；3. 揭示了PGE2和PGF2α作为新型胰岛素增敏剂的新分子机制。研究者首先检测了不同胰岛素抵抗小鼠模型中BAT的m6A甲基转移酶水平，发现胰岛素抵抗小鼠BAT中METTL14高表达，提示其与胰岛素敏感性负相关。进一步通过特异性敲除小鼠BAT中的METTL14，结果显示，敲除后小鼠全身多种代谢组织的胰岛素敏感性显著提升。这表明METTL14的缺失能够通过BAT与其他代谢组织的相互作用改善胰岛素敏感性，且不依赖于UCP1的产热功能。通过脂质组学分析，研究者发现，在METTL14缺失的小鼠棕色脂肪组织及人源性棕色脂肪细胞中，PGE2和PGF2α的水平显著升高。进一步研究表明，PGE2和PGF2α能够显著增强代谢细胞的胰岛素敏感性。在肥胖小鼠模型中注射这两种前列腺素，表现出胰岛素增敏及抗肥胖的表型特征，并伴随白色脂肪组织的米色化现象。值得注意的是，PGE2和PGF2α的血液水平在肥胖及胰岛素抵抗人体中与胰岛素敏感性呈显著正相关。机制研究进一步揭示，PGE2和PGF2α通过特异性GPCR介导的信号通路，抑制AKT磷酸酶的活性，从而提高胰岛素敏感性。模式图（Credit: Cell Metabolism）为了进一步研究m6A如何调控BAT中前列腺素的合成，研究者结合基因组学和m6A甲基化组学，发现METTL14的缺失通过降低m6A甲基化水平，增强了前列腺素合成酶基因的稳定性，增加了其表达。综上所述，该研究揭示了m6A通过调控前列腺素在棕色脂肪中的合成，进而影响全身代谢的新机制，拓展了m6A及其他表观遗传修饰在代谢调控中的研究思路。模式图（Credit: Cell Metabolism）参考文献 1 SHAMSI, F.; WANG, C. H.; TSENG, Y. H. The evolving view of thermogenic adipocytes - ontogeny, niche and function. Nat Rev Endocrinol, v. 17, n. 12, p. 726-744, Dec 2021. ISSN 1759-5029 (Print) 1759-5029. 2 CYPESS, A. M. Reassessing Human Adipose Tissue. N Engl J Med, v. 386, n. 8, p. 768-779, Feb 24 2022. ISSN 0028-4793. 3 DE JESUS, D. F. et al. m(6)A mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes. In: (Ed.). Nat Metab. Germany, v.1, 2019. p.765-774. ISBN 2522-5812 (Electronic) 2522-5812 (Linking). 4 D, F. D. J. et al. Redox regulation of m(6)A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes. Nat Cell Biol, v. 26, n. 3, p. 421-437, Mar 2024. ISSN 1465-7392. 5 KAHRAMAN, S. et al. m6A mRNA Methylation Regulates Early Pancreatic β-Cell Differentiation. bioRxiv, p. 2023.08.03.551675, 2023. Disponível em: < https://www.biorxiv.org/content/biorxiv/early/2023/08/03/2023.08.03.551675.full.pdf >. https://doi.org/10.1016/j.cmet.2024.08.006 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

信使RNA

2024-09-01

·生物探索

Nat Commun丨潘光锦/单永礼团队揭示METTL3/METTL14维持核仁相分离及功能完整性的新功能

引言核仁是维持细胞功能的关键结构，是rRNA合成和核糖体亚基装配的场所，决定细胞蛋白的合成及细胞稳态。核仁是细胞核内唯一没有膜包裹的亚细胞结构且随着细胞周期发生动态结构变化。目前研究表明，作为一个无膜，且高度动态变化的亚细胞结构，核仁主要通过多种生物大分子的液-液相分离（liquid-liquid phase separation，LLPS）方式维持正常结构和功能。核仁的液-液相分离异常可导致核仁结构和功能异常，进而引发多种疾病的发生，如核仁功能减弱导致细胞生长停滞引起的退行性疾病等；核仁功能增强导致白血病等癌症的发生等。然而，作为细胞内没有膜包裹的亚细胞结构，核仁的正常液-液相分离及核仁结构是如何维持的尚不清楚。 2024年8月21日，中国科学院广州生物医药与健康研究院潘光锦/单永礼团队在Nature Communications上发表了题为 METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation 的研究论文。该研究发现了RNA甲基转移酶复合物METTL3/METTL14具有维持人胚胎干细胞中核仁完整性的新功能。 METTL3/METTL14是已经被证明的经典甲基转移酶复合物（MTC），通过催化mRNA上的N6-腺苷甲基化（m6A）参与多种RNA代谢过程，包括RNA稳定性、剪切、转运和翻译等过程，进而调控多种生物学过程和疾病发生。近期，MTC的非经典作用被报道，在小鼠胚胎干细胞（mESCs）中MTC通过正向调节组蛋白H3上的第9位赖氨酸残基三甲基化（H3K9me3）进而调控异染色质和沉默逆转录病毒元件。此项研究发现在人胚胎干细胞中敲除METTL3或METTL14后，并没有导致传统认为的mRNA变化，而是引起核仁结构和功能的剧烈异常，包括核仁变小、数目异常增多、rRNA合成减少、核糖体装配障碍、核仁功能异常导致的核仁应激导致的细胞生长停滞等。进一步发现，缺失METTL3或METTL14后，彻底破坏了核仁的液-液相分离，从而核仁不能形成完整且规则的由多种大分子相分离形成的正常多层级聚集体结构。随后，研究发现在METTL3/METTL14缺陷的细胞中，催化H3K9me3的甲基转移酶SUV39H1/H2蛋白显著升高，导致H3K9me3在整个核仁中积累和浸润，并损害LLPS。从机制上说，METTL3/METTL14复合物作为CRL4 E3泛素连接酶的必要接头，靶向SUV39H1/H2并促进其多泛素化和蛋白酶体降解，从而阻止H3K9me3在核仁中的积累，并维持其正常的LLPS和结构。 METTL3/METTL14维持人胚胎干细胞中核仁完整性的模式图（Credit: Nature Communications）这些新的发现揭示METTL3/METTL14虽然作为经典的mRNA修饰酶，但在维持核仁的相分离和功能方面发挥关键作用。该发现不仅揭示了METTL3/METTL14维持细胞功能的一个从未报道的机制和作用，而且也有助于体现核仁这样一个无膜亚细胞结构如何维持其正常结构和功能。参考文献 https://doi.org/10.1038/s41467-024-51742-7 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

信使RNA引进/卖出临床1期临床终止蛋白降解靶向嵌合体