Translation termination factor eRF3 associates with eRF1 and plays a pivotal role in translation termination.  eRF3 also has significant roles in post-termination events; ribosome recycling and mRNA decay, through its interaction with PABP.  Thus, eRF3 is a multifunctional regulator of gene expression.  In addition, eRF3 functions in the regulation of cell death.  eRF3 is cleaved by some protease(s) into processed isoform of eRF3 (p-eRF3), which interacts with the inhibitors of apoptosis proteins (IAPs).  Through titration of IAP, p-eRF3 activates caspases and promotes apoptosis.  However, a physiological significance of p-eRF3 remains unclear.

In this study, we analyzed a status of eRF3 during stress and apoptosis to reveal a mechanism of p-eRF3 to regulate apoptosis in living cells.

Here, we show that;

1) eRF3 is targeted
for caspase-mediated proteolytic cleavage and degradation during apoptosis.  The decrease in the amount of eRF3 caused by the caspase-mediated degradation contributes to the inhibition of translation during apoptosis. This is the first report showing that eRF3 could serve as a target in the regulation of gene expression.

2) p-eRF3 is produced by Calpain.  Furthermore, p-eRF3 localizes to the nucleus to interact with the ARF tumor suppressor.  These results suggest that p-eRF3 also has some roles in regulating cell death in the nucleus.

Our finding reveals a unique nature of eRF3 that is subject to distinct proteases during stress and apoptosis, resulting in altered arrays in gene expression and apoptosis.  This uncovers a novel function of eRF3, which has been primarily investigated for its role in translation termination.