Wang Lu, Liang Yu, Lin Rongzhi, Xiong Qiuchan, Yu Peng, Ma Jieyi, Cheng Maosheng, Han Hui, Wang Xiaochen, Wang Ganping, Liang Fengyin, Pei Zhong, Chen Demeng, Yuan Quan, Jiang Yi-Zhou, Lin Shuibin
Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong 518060, PR China.
Genes Dis. 2020 Jul 17;9(1):268-274. doi: 10.1016/j.gendis.2020.07.004. eCollection 2022 Jan.
Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA mA methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins. Functionally, we found that Mettl5 knockout in mESCs leads to the abnormal craniofacial and nervous development. Moreover, using Mettl5 knockout mouse model, we further demonstrated that Mettl5 knockout mice exhibit intellectual disability, recapitulating the human phenotype. Mechanistically, we found that Mettl5 maintains brain function and intelligence by regulating the myelination process. Our study uncovered the causal correlation between mis-regulated 18S rRNA mA modification and neural function defects, supporting the important physiological functions of rRNA modifications in human diseases.
核糖体RNA（rRNA）占细胞总RNA的80%以上，然而rRNA修饰的生理功能却知之甚少。18S rRNA mA甲基转移酶METTL5的突变会导致患者出现智力障碍、小头畸形和面部畸形，但其潜在机制却鲜为人知。在本研究中，我们鉴定了METTL5蛋白复合物，并揭示METTL5主要与RNA结合蛋白和核糖体蛋白相互作用。在功能上，我们发现mESC中Mettl5基因敲除会导致颅面和神经发育异常。此外，利用Mettl5基因敲除小鼠模型，我们进一步证明Mettl5基因敲除小鼠表现出智力障碍，重现了人类表型。在机制上，我们发现Mettl5通过调节髓鞘形成过程来维持脑功能和智力。我们的研究揭示了18S rRNA mA修饰失调与神经功能缺陷之间的因果关系，支持了rRNA修饰在人类疾病中的重要生理功能。
