HRD1-mediated METTL14 degradation regulates m⁶A mRNA modification to suppress ER proteotoxic liver disease.

ABSTRACT: 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 N⁶-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3' UTR N⁶-methyladenosine (m⁶A) 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 ubi

SUBMITTER: Wei J 

PROVIDER: S-EPMC8751812 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature