Alpha1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and the most frequent inherited indication for liver failure and transplantation in the pediatric population. However, the clinical course of AATD-related liver disease is highly variable. The majority of infants with homozygous severe AATD (PiZZ) clinically recover in early childhood through the unknown adaptive mechanisms. Epidemiological studies give rise to three outstanding questions in the field. They are: (1) What are the mechanisms of adaptation to the misfolded AAT accumulation in the lumen of ER? (2) Do the mechanisms of adaptation only response to misfolded AAT or also target other unfolded proteins? and (3) Can we design therapeutic strategies to directly use these mechanisms of adaptation? Here, we identified a novel alpha1-antitrypsin deficiency adaptive mechanism, ER proteotoxic stress-m6A pathway or ERm6A : Unfolded Alpha1-antitrypsin protein accumulation induces N6-adenosine-methyltransferase 14 (METTL14) elevation to increase m6A mRNA methylation of C/EBP Homologous Protein (CHOP), which suppresses CHOP translation and reduces expression of its downstream pro-apoptotic target genes, apoptosis and liver injury. We propose that ERm6A regulates ER proteotoxic stress at the epitranscriptional level, through a mechanism that is distinct from any other previously described ER proteotoxic stress-associated signaling pathway, including the well-known canonical (transcriptional and translational level) UPR pathway. We will test the central hypothesis that METTL14, induced by unfolded protein accumulation, suppresses cell death and liver hepatotoxicity (Aim 1.1) by modulating CHOP 5′ UTR m6A modification (Aim 1.2). This proposal addresses the mission of the NICHD by rigorously investigating the molecular mechanisms of AATD-induced liver injury with the potential to improve health for large numbers of children.
|Effective start/end date||6/1/21 → 5/31/23|
- National Institute of Child Health and Human Development (1R21HD104904-01)