The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Life Sciences Institute, Zhejiang University, Hangzhou, China.
Cell Death Dis. 2024 Oct 1;15(10):714. doi: 10.1038/s41419-024-07093-8.
MAT2B works together with MAT2A to synthesize S-Adenosyl methionine (SAM) as the primary methyl donor. MAT2B, despite lacking catalytic activity, exerts regulatory control over the enzymatic activity of MAT2A. In addition to the enzymatic activity regulation, we find that, in an NADP-dependent manner, MAT2B binds and stabilizes MAT2A. Disruption of the cellular NADP remodels the protein level of MAT2A. The pentose phosphatase pathway regulates the level of MAT2A protein through the interaction of NADP with MAT2B. Additionally, MAT2B-MAT2A interaction regulates the mRNA m6A modification and stability. In liver tumors, the Mat2a mRNA level is elevated but the protein level is decreased by the restricted NADP. Blocking the interaction between MAT2B and MAT2A by the keto diet can suppress liver tumor growth. These findings reveal that MAT2B is essential for regulating the protein levels of MAT2A and connecting SAM synthesis to mRNA m6A.
MAT2B 与 MAT2A 合作合成 S-腺苷甲硫氨酸（SAM）作为主要甲基供体。MAT2B 虽然缺乏催化活性，但对 MAT2A 的酶活性具有调节控制作用。除了酶活性调节外，我们发现 MAT2B 以依赖 NADP 的方式结合并稳定 MAT2A。细胞内 NADP 的破坏重塑了 MAT2A 的蛋白水平。戊糖磷酸途径通过 NADP 与 MAT2B 的相互作用来调节 MAT2A 蛋白的水平。此外，MAT2B-MAT2A 相互作用调节 mRNA m6A 的修饰和稳定性。在肝癌中，Mat2a mRNA 水平升高，但由于 NADP 的限制，蛋白水平降低。通过生酮饮食阻断 MAT2B 和 MAT2A 之间的相互作用可以抑制肝癌的生长。这些发现表明 MAT2B 对于调节 MAT2A 的蛋白水平以及将 SAM 合成与 mRNA m6A 连接至关重要。
