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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 N6-methyladenosine (m6A) RNA modification, is implicated in development, but its role in most diseases is unknown. Here, we show that Mettl3 and m6A 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 m6A modification and translation. Thus, Mettl3 promotes ADPKD and links methionine utilization to epitranscriptomic activation of proliferation and cyst growth.

Original languageEnglish (US)
Pages (from-to)1234-1247.e7
JournalCell Metabolism
Volume33
Issue number6
DOIs
StatePublished - Jun 1 2021

Keywords

  • AVPR2
  • c-Myc
  • m6A mRNA methylation
  • methionine
  • METTL3
  • mRNA translation
  • N-methyladenosine
  • polycystic kidney disease
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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