title: Phenformin activates the unfolded protein response in an AMP-activated protein kinase (AMPK)-dependent manner.
abstract: BACKGROUND
  The cross-talk between UPR activation and metabolic stress remains largely unclear.
  
  
  RESULTS
  Phenformin treatment activates the IRE1α and PERK pathways in an AMPK-dependent manner.
  
  
  CONCLUSIONS
  AMPK is required for phenformin-mediated IRE1α and PERK activation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Graduate Program in Biochemistry, Molecular and Cell Biology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Haibo
authors.initials: H
authors.lastname: Sha
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
mesh_terms: D041721:3T3-L1 Cells; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D055786:Gene Knockout Techniques; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D010629:Phenformin / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D000071701:Regulatory Factor X Transcription Factors; D012265:Ribonucleotides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D010629:Phenformin; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D019892:eIF-2 Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; D004722:Endoribonucleases; C031143:AICA ribonucleotide
keywords: AMP-activated Protein Kinase (AMPK); Anti-diabetic Drug; Biguanide; Endoplasmic Reticulum Stress; Energy Metabolism; IRE1α; PERK; Signaling; Unfolded Protein Response
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