小柯机器人

美国德克萨斯西南医学中心Vishal Patel和梅奥诊所Eduardo N. Chini研究团队合作在研究中取得进展。他们发现甲硫氨酸-Mettl3-N6-甲基腺嘌呤通路促进多囊肾病。2021年4月13日，国际学术期刊《细胞-代谢》在线发表了这一成果。

研究人员发现在人和小鼠常染色体显性遗传性多囊肾病（ADPKD）样品中Mettl3和m6A的含量增加，并且肾脏特异性表达Mettl3会产生管状囊肿。相反，在三个直系ADPKD小鼠模型中，Mettl3缺失减缓了囊肿的生长。

有趣的是，在ADPKD模型中，蛋氨酸和S-腺苷蛋氨酸（SAM）的含量有所上升。此外，蛋氨酸和SAM诱导Mettl3表达并加剧离体囊肿的生长，而通过饮食限制蛋氨酸摄入则会减弱小鼠ADPKD。最后，Mettl3通过诱导c-Myc表达和Avpr2 mRNA m6A修饰增强来激活促进囊肿的c-Myc和cAMP途径。因此，Mettl3促进ADPKD的发生，并将蛋氨酸的利用、转录组激活增加和囊肿生长相关联。

据介绍，ADPKD是一种常见的单基因疾病，其特征是许多肾脏囊肿逐渐扩大。Mettl3是催化N6-甲基腺苷（m6A）RNA修饰的甲基转移酶，与发育有关，但其在许多疾病中的作用尚不清楚。

附：英文原文

Title: A methionine-Mettl3-N6-methyladenosine axis promotes polycystic kidney disease

Author: Harini Ramalingam, Sonu Kashyap, Patricia Cobo-Stark, Andrea Flaten, Chun-Mien Chang, Sachin Hajarnis, Kyaw Zaw Hein, Jorgo Lika, Gina M. Warner, Jair M. Espindola-Netto, Ashwani Kumar, Mohammed Kanchwala, Chao Xing, Eduardo N. Chini, Vishal Patel

Issue&Volume: 2021-04-13

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disordermarked by numerous progressively enlarging kidney cysts. Mettl3, a methyltransferasethat catalyzes the abundant N6-methyladenosine (m6A) RNA modification, is implicated in development, but its role in most diseases isunknown. Here, we show that Mettl3 and m6A levels are increased in mouse and human ADPKD samples and that kidney-specific transgenicMettl3 expression produces tubular cysts. Conversely, Mettl3 deletion in three orthologous ADPKD mouse models slows cyst growth. Interestingly,methionine and S-adenosylmethionine (SAM) levels are also elevated in ADPKD models.Moreover, methionine and SAM induce Mettl3 expression and aggravate ex vivo cyst growth, whereas dietary methionine restriction attenuates mouse ADPKD. Finally,Mettl3 activates the cyst-promoting c-Myc and cAMP pathways through enhanced c-Myc and Avpr2 mRNA m6A modification and translation. Thus, Mettl3 promotes ADPKD and links methionine utilizationto epitranscriptomic activation of proliferation and cyst growth.

DOI: 10.1016/j.cmet.2021.03.024

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00131-5

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