GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses
van Leyen, K
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CitationHotokezaka, Y, I Katayama, K van Leyen, and T Nakamura. 2015. “GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses.” Cell Death & Disease 6 (4): e1719. doi:10.1038/cddis.2015.90. http://dx.doi.org/10.1038/cddis.2015.90.
AbstractThe signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3β (GSK-3β)-dependent downregulation of γ-taxilin and nascent polypeptide-associated complex α-subunit (αNAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of γ-taxilin or αNAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by γ-taxilin or αNAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3β-dependent tau hyperphosphorylation and cleavage in neuronal cells, but γ-taxilin ablation induced tau hyperphosphorylation alone and αNAC ablation induced neither changes. Notably, downregulation of γ-taxilin and αNAC occurs in the brain of patients with Alzheimer's disease. These results suggest that GSK-3β-dependent downregulation of γ-taxilin and αNAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases.
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