A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression.
A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression.
复制标题
DOI：
10.7554/elife.87283
复制
发表时间：
2023-08-17
期刊：
影响因子：
7.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Yan C;Xiong J;Zhou Z;Li Q;Gao C;Zhang M;Yu L;Li J;Hu MM;Zhang CS;Cai C;Zhang H;Zhang J
甲基转移酶复合体(MTC)通过甲基转移酶复合体(MTC)对RNA的N6-甲基腺苷(M6A)甲基化，其核心成分包括METTL3-METTL14异源二聚体和Wilms的肿瘤相关蛋白(WTAP)，在乳腺癌的发生中起重要作用，但其潜在的调控机制仍不清楚。在这里，我们鉴定了一种新的裂解形式METTL3a(METTL3的残基239-580)。我们发现METTL3a是METTL3-WTAP相互作用、RNA m6A沉积以及癌细胞增殖所必需的。从力学上讲，我们发现METTL3a在METTL3-METTL3相互作用中是必不可少的，这是WTAP在MTC招募的先决条件。对m6A测序数据的分析表明，METTL3a的缺失在全球范围内扰乱了m6A的沉积，而METTL3a通过m6A介导的抑制TMEM127的表达介导了哺乳动物雷帕霉素(MTOR)的激活靶点。此外，我们发现METTL3的切割是由蛋白酶体以mTOR依赖的方式介导的，揭示了METTL3a和mTOR信号之间的正调控反馈。我们的发现揭示了METTL3a是MTC的重要组成部分，并提示METTL3a-mTOR轴是乳腺癌的潜在治疗靶点。
N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3–METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239–580 of METTL3). We find that METTL3a is required for the METTL3–WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3–METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mammalian target of rapamycin (mTOR) activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a–mTOR axis as a potential therapeutic target for breast cancer.