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- W3189791323 abstract "Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers ER proteotoxic stress and the unfolded protein response (UPR) for stress adaptation. The failure in this adaptation induces cell apoptosis and leads to tissue/organ damage-associated diseases, such as alpha-1 antitrypsin (AAT) deficiency, a genetic liver disease caused by accumulation of the misfolded AAT protein. The molecular switches underlying how the UPR, which initiates both apoptotic and adaptive pathways, selects for stress adaptation over apoptosis remain as biomedical mysteries. Here we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase 14 (METTL14) expression. METTL14 catalyzes C/EBP Homologous Protein (CHOP) mRNA methylation to suppress its protein expression, which consequently inhibits the expression of its downstream pro-apoptotic target genes and protects cells from CHOP-mediated apoptosis. UPR induces METTL14 expression at post-transcription level 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 AAT deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protected METTL14 knockout mice from ER proteotoxic stress induced liver damage. Our study revealed a novel crosstalk between ER stress and mRNA N6-adenosine-methylation (m 6 A) pathways, the ER stress-m6A (ERm6A) pathway, as a preciously unappreciated mechanism for ER stress adaptation to proteotoxicity." @default.
- W3189791323 created "2021-08-16" @default.
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- W3189791323 date "2021-01-01" @default.
- W3189791323 modified "2023-10-14" @default.
- W3189791323 title "HRD1-Mediated METTL14 Degradation Regulates M <sup>6</sup>a mRNA Modification to Suppress ER Proteotoxic Liver Damage" @default.
- W3189791323 doi "https://doi.org/10.2139/ssrn.3832981" @default.
- W3189791323 hasPublicationYear "2021" @default.
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