Key Laboratory of Immune Response and Immunotherapy, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.
Nanfang Hospital, Southern Medical University, Guangzhou, China.
Nat Commun. 2024 Aug 21;15(1):7186. doi: 10.1038/s41467-024-51742-7.
Nucleoli are fundamentally essential sites for ribosome biogenesis in cells and formed by liquid-liquid phase separation (LLPS) for a multilayer condensate structure. How the nucleoli integrity is maintained remains poorly understood. Here, we reveal that METTL3/METTL14, the typical methyltransferase complex catalyzing N6-methyladnosine (mA) on mRNAs maintain nucleoli integrity in human embryonic stem cells (hESCs). METTL3/METTL14 deficiency impairs nucleoli and leads to the complete loss of self-renewal in hESCs. We further show that SUV39H1/H2 protein, the methyltransferases catalyzing H3K9me3 were dramatically elevated in METTL3/METTL14 deficient cells, which causes an accumulation and infiltration of H3K9me3 across the whole nucleolus and impairs the LLPS. Mechanistically, METTL3/METTL14 complex serves as an essential adapter for CRL4 E3 ubiquitin ligase targeting SUV39H1/H2 for polyubiquitination and proteasomal degradation and therefore prevents H3K9me3 accumulation in nucleoli. Together, these findings uncover a previously unknown role of METTL3/METTL14 to maintain nucleoli integrity by facilitating SUV39H1/H2 degradation in human cells.
核仁是细胞中核糖体生物发生的基本必需场所，通过液-液相分离（LLPS）形成多层凝聚物结构。核仁完整性如何维持仍知之甚少。在这里，我们揭示了典型的甲基转移酶复合物 METTL3/METTL14 可催化 mRNA 上的 N6-甲基腺苷（m6A），以维持人类胚胎干细胞（hESC）中的核仁完整性。METTL3/METTL14 缺失会破坏核仁，并导致 hESC 完全丧失自我更新能力。我们进一步表明，SUV39H1/H2 蛋白，即催化 H3K9me3 的甲基转移酶，在 METTL3/METTL14 缺失的细胞中显著升高，导致 H3K9me3 在整个核仁中积累和渗透，并破坏 LLPS。在机制上，METTL3/METTL14 复合物作为 CRL4 E3 泛素连接酶的必需接头，靶向 SUV39H1/H2 进行多泛素化和蛋白酶体降解，从而防止 H3K9me3 在核仁中积累。总之，这些发现揭示了 METTL3/METTL14 通过促进 SUV39H1/H2 在人类细胞中的降解来维持核仁完整性的先前未知作用。
