Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death.
Up-regulation of several stress proteins such as heat-shock proteins and glucose-regulated proteins participate in tolerance against environmental stress. Previously, we found that protein-disulfide isomerase (PDI) is specifically up-regulated in response to hypoxia/brain ischemia in astrocytes. In addition, the overexpression of this gene into neurons protects against apoptotic cell death induced by hypoxia/brain ischemia. To address the detailed function of PDI, we screened for proteins that interact with PDI using the yeast two-hybrid system. We report here that PDI interacts with ubiquilin, which has a ubiquitin-like domain and a ubiquitin-associated domain. Interestingly, ubiquilin is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction. In hypoxia-treated glial cells, the endogenous ubiquilin and PDI were almost completely co-localized, suggesting that ubiquilin is an endoplasmic reticulum-associated protein. Overexpression of this gene in neuronal cells resulted in significant inhibition of the DNA fragmentation triggered by hypoxia, but not that induced by nitric oxide or staurosporine. Moreover, ubiquilin has the ability to attenuate CHOP induction by hypoxia. These observations suggested that ubiquilin together with PDI have critical functions as regulatory proteins for CHOP-mediated cell death, and therefore up-regulation of these proteins may result in acquisition of tolerance against ischemic stress in glial cells.
Ko
Han Seok
HS
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Uehara
Takashi
T
Nomura
Yasuyuki
Y
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins; D002470:Cell Survival; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D017931:DNA Primers; D014157:Transcription Factors; C107792:UBQLN1 protein, human; D051742:Transcription Factor CHOP; D019704:Protein Disulfide-Isomerases