Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death

Han Seok Ko, Takashi Uehara, Yasuyuki Nomura

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)35386-35392
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number38
DOIs
Publication statusPublished - Sep 20 2002
Externally publishedYes

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Protein Disulfide-Isomerases
Endoplasmic Reticulum Stress
Cell death
Cell Death
Neuroglia
Brain Hypoxia-Ischemia
Ubiquitin
Heat-Shock Proteins
Brain
Proteins
Up-Regulation
Genes
Two-Hybrid System Techniques
Staurosporine
DNA Fragmentation
Hybrid systems
Astrocytes
Endoplasmic Reticulum
Yeast
Neurons

ASJC Scopus subject areas

  • Biochemistry

Cite this

Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. / Ko, Han Seok; Uehara, Takashi; Nomura, Yasuyuki.

In: Journal of Biological Chemistry, Vol. 277, No. 38, 20.09.2002, p. 35386-35392.

Research output: Contribution to journalArticle

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