Phenformin Activates Unfolded Protein Response in an AMP-Activated Protein Kinase (AMPK)-Dependent Manner

Activation of unfolded protein response (UPR) is associated with the disruption of endoplasmic reticulum (ER) homeostasis and has been implicated in the pathogenesis of many human metabolic diseases, including obesity and type-2 diabetes. However, the nature of the signals activating UPR under these conditions remains largely unknown. Using a method that we recently optimized to directly measure UPR sensor activation, here we screen the effect of various metabolic drugs on UPR activation and show that an antidiabetic drug phenformin activates UPR sensors IRE1α and PERK via both ER-dependent and -independent manners. Mechanistically, AMPK activation is required but not sufficient to initiate phenformin-mediated IRE1α and PERK activation, suggesting the involvement of additional factor(s). Interestingly, activation of the IRE1α, but not the PERK pathway, is partially responsible for the cytotoxic effect of phenformin. Together, our data show the existence of a noncanonical UPR whose activation requires cytosolic kinase AMPK, adding another layer of complexity to UPR activation under metabolic stress.