GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses

The signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3 beta (GSK-3 beta)-dependent downregulation of gamma-taxilin and nascent polypeptide-associated complex alpha-subunit (alpha NAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of gamma-taxilin or alpha NAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by gamma-taxilin or alpha NAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3 beta-dependent tau hyperphosphorylation and cleavage in neuronal cells, but gamma-taxilin ablation induced tau hyperphosphorylation alone and alpha NAC ablation induced neither changes. Notably, downregulation of gamma-taxilin and alpha NAC occurs in the brain of patients with Alzheimer's disease. These results suggest that GSK-3 beta-dependent downregulation of gamma-taxilin and alpha NAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases.