GRP78 compartmentalized redistribution in Pb-treated glia: Role of GRP78 in lead-induced oxidative stress

Yongchang Qian, Ying Zheng, Kenneth S. Ramos, Evelyn Tiffany-Castiglioni

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Glucose-regulated protein of 78 kDa (GRP78) is an endoplasmic reticulum (ER) molecular chaperone functioning in protein folding, assembly and trafficking. GRP78 also plays a role in protection against cytotoxicity and apoptosis induced by environmental insults. Our previous study showed that lead (Pb) directly targets GRP78 by binding to the protein and increasing GRP78 levels. In this study, the effect of Pb on compartmentalized distribution of GRP78 in living cells was examined. A rat GRP78-EGFP fusion protein and EGFP were transiently expressed in astrocytoma cells exposed to 5 μM Pb acetate or 50 μM CuSO4 and fluorescence signals were captured. Control cells expressing EGFP showed a homogeneous distribution of EGFP that was not changed by Pb or Cu treatment. Cells expressing GRP78-EGFP showed a compartmentalized, non-homogeneous distribution of GRP78-EGFP in the cytosol. The redistribution of GRP78-EGFP fluorescent bodies was observed in cells exposed to Pb for 10 h, but not 5 h. Redistribution was also observed in cells exposed to 50 μM Cu for 5 or 10 h. To assess GRP78 function, GRP78 was depleted with dsRNAi oligos in rat C6 glioma cells. GRP78 depletion significantly increased the sensitivity of cells to Pb exposure as indicated by the generation of reactive oxygen species (ROS). These data suggest that Pb directly targets GRP78 and induces its compartmentalized redistribution in living cells and that GRP78 plays a protective role in Pb neurotoxicity.

Original languageEnglish (US)
Pages (from-to)267-275
Number of pages9
JournalNeuroToxicology
Volume26
Issue number2
DOIs
StatePublished - Mar 2005
Externally publishedYes

Keywords

  • Astroglia
  • GRP78
  • Lead
  • Protein redistribution
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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