Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center Dallas, TX 75390, USA.
Department of Anesthesiology and Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
Cell Metab. 2021 Jun 1;33(6):1234-1247.e7. doi: 10.1016/j.cmet.2021.03.024. Epub 2021 Apr 13.
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder marked by numerous progressively enlarging kidney cysts. Mettl3, a methyltransferase that catalyzes the abundant N-methyladenosine (mA) RNA modification, is implicated in development, but its role in most diseases is unknown. Here, we show that Mettl3 and mA levels are increased in mouse and human ADPKD samples and that kidney-specific transgenic Mettl3 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 mA modification and translation. Thus, Mettl3 promotes ADPKD and links methionine utilization to epitranscriptomic activation of proliferation and cyst growth.
常染色体显性多囊肾病（ADPKD）是一种常见的单基因疾病，其特征是大量逐渐增大的肾囊肿。Mettl3 是一种甲基转移酶，可催化丰富的 N6-甲基腺苷（m6A）RNA 修饰，参与发育过程，但在大多数疾病中的作用尚不清楚。在这里，我们表明 Mettl3 和 mA 水平在小鼠和人类 ADPKD 样本中增加，并且肾脏特异性转基因 Mettl3 表达可产生管状囊肿。相反，在三种同源 ADPKD 小鼠模型中敲除 Mettl3 可减缓囊肿生长。有趣的是，ADPKD 模型中的蛋氨酸和 S-腺苷甲硫氨酸（SAM）水平也升高。此外，蛋氨酸和 SAM 诱导 Mettl3 表达并加重体外囊肿生长，而饮食中蛋氨酸限制可减轻小鼠 ADPKD。最后，Mettl3 通过增强 c-Myc 和 Avpr2 mRNA m6A 修饰和翻译来激活促进囊肿形成的 c-Myc 和 cAMP 途径。因此，Mettl3 促进了 ADPKD 的发生，并将蛋氨酸利用与增殖和囊肿生长的表观转录组激活联系起来。
