A methionine-Mettl3-N-methyladenosine axis promotes polycystic kidney disease
| Autor: | Sonu Kashyap, Chao Xing, Patricia Cobo-Stark, Jorgo Lika, Sachin Hajarnis, Harini Ramalingam, Kyaw Zaw Hein, Gina M. Warner, Mohammed Kanchwala, Eduardo N. Chini, Ashwani Kumar, Vishal Patel, Jair Machado Espindola-Netto, Chun Mien Chang, Andrea Flaten |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Methyltransferase Physiology Transgene Autosomal dominant polycystic kidney disease Biology urologic and male genital diseases Kidney cysts 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Polycystic kidney disease Cyst Molecular Biology Methionine urogenital system Cell Biology medicine.disease female genital diseases and pregnancy complications 030104 developmental biology Endocrinology chemistry N6-Methyladenosine medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Cell Metabolism. 33:1234-1247.e7 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2021.03.024 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|