O-linked β-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3β-dependent manner

Zahra Kazemi, Hana Chang, Sarah Haserodt, Cathrine McKen, Natasha E. Zachara

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate the mechanisms by which O-linked β-N-acetylglucosamine modification of nucleocytoplasmic proteins (O-GlcNAc) confers stress tolerance to multiple forms of cellular injury, we explored the role(s) of O-GlcNAc in the regulation of heat shock protein (HSP) expression. Using a cell line in which deletion of the O-GlcNAc transferase (OGT; the enzyme that adds O-GlcNAc) can be induced by 4-hydroxytamoxifen, we screened the expression of 84 HSPs using quantitative reverse transcriptase PCR. In OGT null cells the stress-induced expression of 18 molecular chaperones, including HSP72, were reduced. GSK-3β promotes apoptosis through numerous pathways, including phosphorylation of heat shock factor 1 (HSF1) at Ser303 (Ser(P) 303 HSF1), which inactivates HSF1 and inhibits HSP expression. In OGT null cells we observed increased Ser(P)303 HSF1; conversely, in cells in which O-GlcNAc levels had been elevated, reduced Ser(P)303 HSF1 was detected. These data, combined with those showing that inhibition of GSK-3β in OGT null cells recovers HSP72 expression, suggests that O-GlcNAc regulates the activity of GSK-3β. In OGT null cells, stress-induced inactivation of GSK-3β by phosphorylation at Ser9 was ablated providing a molecular basis for these findings. Together, these data suggest that stress-induced GlcNAcylation increases HSP expression through inhibition of GSK-3β.

Original languageEnglish (US)
Pages (from-to)39096-39107
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number50
DOIs
StatePublished - Dec 10 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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