A methionine-Mettl3-N-6-methyladenosine axis promotes polycystic kidney disease

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-6-methyladenosine (m(6)A) RNA modification, is implicated in development, but its role in most diseases is unknown. Here, we show that Mettl3 and m(6)A 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 m(6)A modification and translation. Thus, Mettl3 promotes ADPKD and links methionine utilization to epitranscriptomic activation of proliferation and cyst growth.

Automated summary

Mettl3 and m(6)A levels are increased in ADPKD, and Mettl3 deletion slows cyst growth, while methionine and SAM are associated with ADPKD development. Furthermore, Mettl3 activates cyst-promoting pathways in ADPKD through epitranscriptional modifications.