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

Mol Cell. 2021 Dec 16;81(24):5052-5065.e6. doi: 10.1016/j.molcel.2021.10.028. Epub 2021 Nov 29.


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 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 modification pathways, termed the ERm6A pathway, for ER stress adaptation to proteotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • 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
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism
  • alpha 1-Antitrypsin Deficiency / complications
  • alpha 1-Antitrypsin Deficiency / enzymology
  • alpha 1-Antitrypsin Deficiency / genetics


  • DDIT3 protein, human
  • Ddit3 protein, mouse
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin
  • Transcription Factor CHOP
  • METTL14 protein, human
  • Methyltransferases
  • Mettl14 protein, mouse
  • SYVN1 protein, human
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Adenine
  • 6-methyladenine