A new study sheds light on how protein misfolding and accumulation in the endoplasmic reticulum (ER)—which is a hallmark of many diseases, including alpha-1 antitrypsin (AAT) deficiency (AATD)—triggers an adaptive response in cells, and how targeting elements of that response could potentially help tackle diseases such as AATD. The research was published in Molecular Cell.
According to the study, the accumulation of misfolded proteins, such as misfolded AAT as in the case of AATD, induces the expression of the METTL14 protein. This protein induces the decay of the mRNA of the CHOP protein. CHOP normally triggers the expression of genes encoding proteins that are involved in programmed cell death or apoptosis.
So when METTL14 is active, due to the accumulation of misfolded proteins, CHOP is inactive and cells activate their adaptive response instead of going into apoptosis.
Supporting this proposed mechanism, the results of the study also showed that mice that have no METTL14 in their liver are highly susceptible to AATD-induced ER proteotoxic stress and liver injury due to cell death. Moreover, deletion of CHOP in the liver of these animals protects them from ER-stress-induced liver damage.
Most interestingly, it has recently been found that the gene coding for CHOP is highly upregulated in young patients with AATD homozygous for the Z allele (also known as the PiZ allele), which causes the most common form of the disease.
Read more about AATD etiology.
According to the authors, this study reveals a possible molecular mechanism by which CHOP expression is upregulated during PiZ pathogenesis by suppressing METTL14-mediated CHOP mRNA modification.
“In addition to CHOP, transcription factors including ATF6 and Xbp-1 play critical roles in ER proteotoxic stress response,” the researchers wrote. “Future studies are needed to identify additional downstream targets of METTL14 in ER stress adaptation and their involvement in proteotoxicity-induced diseases including AAT-induced liver disease”.
Wei J, Harada BT, Lu D, et al. HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease. Mol Cell. 2021;16;81(24):5052-5065.e6. doi:10.1016/j.molcel.2021.10.028