| First Author | Wei J | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 24 | Pages | 5052-5065.e6 |
| PubMed ID | 34847358 | Mgi Jnum | J:321938 |
| Mgi Id | MGI:6874637 | Doi | 10.1016/j.molcel.2021.10.028 |
| Citation | Wei J, et al. (2021) HRD1-mediated METTL14 degradation regulates m(6)A mRNA modification to suppress ER proteotoxic liver disease. Mol Cell 81(24):5052-5065.e6 |
| abstractText | Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers an unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here, we discovered that accumulation of unfolded/misfolded proteins selectively induces N(6)-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3' UTR N(6)-methyladenosine (m(6)A) to inhibit its downstream pro-apoptotic target gene expression. UPR induces METTL14 expression by competing against the HRD1-ER-associated degradation (ERAD) machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER-stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m(6)A modification pathways, termed the ERm(6)A pathway, for ER stress adaptation to proteotoxicity. |
