Title: ER Stress‐independent Noncanonical UPR Activation under Phenformin Treatment
Abstract: Activation of unfolded protein response (UPR) is associated with disruption of homeostasis in the endoplasmic reticulum and has been implicated in the pathogenesis of many human diseases including obesity and type‐2 diabetes. However, whether metabolic pathways can directly regulate UPR independently of misfolded protein accumulation and ER stress remains unclear. In a test of various metabolic drugs, we show that activation of UPR sensors can be uncoupled from the ER signals. First, treatment with the antidiabetic drug phenformin activates UPR sensors IRE1α and PERK even in the absence of protein synthesis. Second, phenformin treatment strongly activates a PERK mutant only residing in the cytosol. Mechanistically, kinase activities of both IRE1α and PERK are required for the phenformin effect. Moreover, AMPK activation is required but not sufficient to initiate IRE1α and PERK pathways, suggesting the involvement of additional factor(s) under phenformin treatment. Interestingly, activation of the IRE1α, but not the PERK pathway, may partially mediate the cytotoxic effect of phenformin. Together, these findings demonstrate the existence of a noncanonical UPR where activating signals are derived from the cytosol, adding another layer of complexity to the UPR activation under metabolic stress.
Publication Year: 2013
Publication Date: 2013-04-01
Language: en
Type: article
Indexed In: ['crossref']
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