Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic

Cells contain thousands of proteins that carry out the essential tasks needed for survival. Before they can work, proteins must first fold into specific three-dimensional shapes. The endoplasmic reticulum, a cellular compartment that specializes in properly folding newly made proteins into their native states, is critical for this protein maturation process. If folding-enzymes in the endoplasmic reticulum are not properly balanced with the load of proteins they must fold, the endoplasmic reticulum can be overwhelmed with unfolded proteins that accumulate, leading to ‘endoplasmic reticulum stress’. The cell copes with endoplasmic reticulum stress by triggering the ‘unfolded protein response’ (UPR). This response helps to clear the unfolded proteins by increasing the size of the endoplasmic reticulum and the concentration of folding enzymes within it, and by decreasing the influx of newly made protein into the endoplasmic reticulum. The UPR engages signaling molecules in the endoplasmic reticulum membrane, among them two signaling enzymes called IRE1 and PERK. Drugs that activate these signaling enzymes could help the cell to deal with unfolded proteins, prevent toxicity resulting from endoplasmic reticulum stress, and ward off the diseases that result from it. Mendez, Alfaro, Morales-Soto et al. developed a small molecule, called IPA (short for IRE1/PERK Activator), that was designed to bind to and activate IRE1. Serendipitously, IPA not only activated IRE1 but also activated PERK. Surprisingly, PERK activation was only observed at low IPA concentrations in which IPA occupied the active sites in only a few PERK molecules, whereas at higher concentrations and full occupancy IPA completely inhibited PERK. Mendez, Alfaro, Morales-Soto et al. proposed that, under conditions of partial IPA occupancy, a minority of IPA-bound PERK molecules assume an activated state that propagates to adjacent PERK molecules that have no IPA bound to them, and activates them. Similar dose-dependent activation was previously observed for a clinically used drug designed to inhibit a similar signaling enzyme that is important in cancer progression. Together with the observations of Mendez, Alfaro, Morales-Soto et al., these results suggest that research into similar treatments must consider that a ‘minimal dose’ can exist, below which drugs may have the opposite effect to what is desired. Further work is still needed to fully understand the mechanisms that produce such behavior.