Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins

• DOI: 10.7554/elife.37168
• Publication Date: 2018-08-07T10:00:14Z
• Authors: Ryan Paxman; Lars Plate; Erik A Blackwood; Chris Glembotski; Evan T Powers; R Luke Wiseman; Jeffery W Kelly
• Keywords: 0301 basic medicine; QH301-705.5; Science; Endoplasmic Reticulum; Small Molecule Libraries; 03 medical and health sciences; Biochemistry and Chemical Biology; Humans; quinone methide; Prodrugs; proteostasis regulator; Biology (General); proteostasis; Phenylpropionates; Q; R; Endoplasmic Reticulum Stress; protein disulfide isomerase; Amides; Activating Transcription Factor 6; HEK293 Cells; cytochrome p450; Unfolded Protein Response; Medicine; reactive cysteine; Signal Transduction

Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule N-(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (147) was previously identified (<xref ref-type="bibr" rid="bib35">Plate et al., 2016</xref>) to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that 147-dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by 147 include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs 147-dependent induction of the ATF6-target gene, BiP, implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with 147. Thus, 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.