Regulation of anisomycin-induced, upstream open reading frame-driven, CHOP translation by AMP-activated protein kinase

Unfolded protein response (UPR) regulates gene expression through transcriptional and translational control and results in ER stress recovery or cell apoptosis. CHOP is one of the components that involves in the ER stress-mediated pathway. Upstream open reading frame (uORF) of the CHOP plays an essential role in controlling the protein expression via translation. We have shown that anisomycin-induced uORF-mediated CHOP translation depends on the phosphorylated eIF4E/S209, eIF2α and 4E-BP1. In this report, we uncovered that AMPK is involved in the induction of uORF-mediated CHOP translation under anisomycin treatment. When moderately activated by anisomycin, AMPK maintains the phosphorylated level of p38 MAPK, Mnk, and eIF4E/S209 by negatively regulate phosphatase PP2Cβ1 activity. When fully activated by AICAR, AMPK inhibits both PP2C β1 and mTOR activities, leading to inability of dissociation of the eIF4E-4EBP1 complex and repression of translation initiation complex formation. Taken together, the present results indicate that anisomycin-activated AMPK plays positive regulatory roles in uORF-mediated CHOP translation.