title: GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses.
abstract: The 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.
authors.affiliation: Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hotokezaka
authors.affiliation: Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Katayama
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: K
authors.initials: K
authors.lastname: van Leyen
authors.affiliation: Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D056811:Unfolded Protein Response; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D018832:Molecular Chaperones; C508884:TXLNG protein, human; D033921:Vesicular Transport Proteins; C096099:nascent-polypeptide-associated complex; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3