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

ABSTRACT: 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 (Plate et al., 2016) 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

SUBMITTER: Paxman R 

PROVIDER: S-EPMC6080950 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature