HRD1-mediated METTL14 degradation regulates m 6 A mRNA modification to suppress ER proteotoxic liver disease

• Published in: Molecular cell 2021-12, Vol.81 (24), p.5052
• Main Authors: Wei, Juncheng, Harada, Bryan T, Lu, Dan, Ma, Ruihua, Gao, Beixue, Xu, Yanan, Montauti, Elena, Mani, Nikita, Chaudhuri, Shuvam M, Gregory, Shana, Weinberg, Samuel E, Zhang, Donna D, Green, Richard, He, Chuan, Fang, Deyu
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - metabolism; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin Deficiency - complications; alpha 1-Antitrypsin Deficiency - enzymology; alpha 1-Antitrypsin Deficiency - genetics; Animals; Apoptosis; Disease Models, Animal; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; HEK293 Cells; Hep G2 Cells; Humans; Liver - enzymology; Liver - pathology; Liver Diseases - enzymology; Liver Diseases - etiology; Liver Diseases - genetics; Liver Diseases - pathology; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; NIH 3T3 Cells; Proteolysis; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 1097-4164

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 -adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3' UTR N -methyladenosine (m 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 A modification pathways, termed the ERm A pathway, for ER stress adaptation to proteotoxicity.