GSE185109
HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease
Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers 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 CHOP mRNA decay through its 3'UTR N6-adenosine methylation (m6A) to inhibit its downstream pro-apoptotic target genes expression.  UPR induces METTL14 expression through competing the HRD1-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 m6A pathways, the ERm6A pathway, for ER stress adaptation to proteotoxicity. Overall design: To investigate the molecular mechanisms underlying how METTL14 protects mice from UPR-induced liver damage, we analyzed the mRNA expression profile in liver from Tm treated METTL14 LKO and WT mice by transcriptome-wide mRNA sequencing.