Abstract
The cross-talk between UPR activation and metabolic stress remains largely unclear. Phenformin treatment activates the IRE1α and PERK pathways in an AMPK-dependent manner. AMPK is required for phenformin-mediated IRE1α and PERK activation. Our findings demonstrate the cross-talk between UPR and metabolic signals. Activation of the 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, we screened the effect of various metabolic drugs on UPR activation and show that the anti-diabetic drug phenformin activates UPR sensors IRE1α and pancreatic endoplasmic reticulum kinase (PERK) in both an ER-dependent and ER-independent manner. Mechanistically, AMP-activated protein kinase (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 PERK) pathway is partially responsible for the cytotoxic effect of phenformin. Together, our data show the existence of a non-canonical UPR whose activation requires the cytosolic kinase AMPK, adding another layer of complexity to UPR activation upon metabolic stress.
Highlights
The cross-talk between unfolded protein response (UPR) activation and metabolic stress remains largely unclear
Our study demonstrates phenformin-induced UPR activation in an AMPK-dependent manner
The downstream outcomes of this phenformin-induced UPR strongly resemble those of the UPR triggered by traditional endoplasmic reticulum (ER) stress inducers, including activation of downstream canonical events of the IRE1␣ and pancreatic endoplasmic reticulum kinase (PERK) pathways such as the requirement of kinase activities of IRE1␣ and PERK, Xbp1 splicing, eIF2␣ phosphorylation, and induction of ER chaperones
Summary
The cross-talk between UPR activation and metabolic stress remains largely unclear. Results: Phenformin treatment activates the IRE1␣ and PERK pathways in an AMPK-dependent manner. AMP-activated protein kinase (AMPK) activation is required but not sufficient to initiate phenformin-mediated IRE1␣ and PERK activation, suggesting the involvement of additional factor(s). Upon accumulation of misfolded proteins in the ER lumen, canonical UPR in mammals is initiated by activation of three major ER transmembrane sensors: IRE1␣, pancreatic endoplasmic reticulum kinase (PERK), and ATF6 [3]. To address whether and how metabolic signals cross-talk with UPR pathways and facilitate UPR activation, we took advantage of a recently developed Phos-tag-based method. This method allows for visual assessment and quantitative. Our study implicates a requirement for AMPK in phenformin-mediated UPR activation and provides a framework for further studies to understand the cross-talk between metabolic signals and UPR activation
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