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O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a

Zahra Kazemi1, Hana Chang, Sarah Haserodt

  • 1Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

The Journal of Biological Chemistry
|October 8, 2010
PubMed

Insights

O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhances cellular stress tolerance by increasing heat shock protein (HSP) expression. This occurs through the inhibition of GSK-3β, a key regulator of apoptosis and HSP expression.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational modification crucial for cellular signaling and stress response.
  • Heat shock proteins (HSPs) are critical molecular chaperones that protect cells from various forms of stress.
  • The interplay between O-GlcNAc and HSP expression in cellular injury response remains incompletely understood.

Purpose of the Study:

  • To elucidate the role of O-GlcNAc modification in regulating heat shock protein (HSP) expression under cellular stress.
  • To investigate the molecular mechanisms linking O-GlcNAc levels to the expression of stress-induced molecular chaperones.

Main Methods:

  • Utilized a cell line with inducible O-GlcNAc transferase (OGT) deletion to assess O-GlcNAc's role.
  • Quantified the expression of 84 HSPs using quantitative reverse transcriptase PCR.
  • Examined the phosphorylation status of GSK-3β and HSF1 in cells with altered O-GlcNAc levels.

Main Results:

  • Deletion of OGT significantly reduced the stress-induced expression of 18 molecular chaperones, including HSP72.
  • OGT-null cells exhibited increased phosphorylation of GSK-3β target site Ser(303) on HSF1, correlating with reduced HSP expression.
  • Elevated O-GlcNAc levels led to decreased Ser(303) HSF1 phosphorylation, while inhibition of GSK-3β restored HSP72 expression in OGT-null cells.
  • Stress-induced phosphorylation and inactivation of GSK-3β at Ser(9) were impaired in OGT-null cells.

Conclusions:

  • O-GlcNAc modification plays a critical role in upregulating HSP expression during cellular stress.
  • The mechanism involves O-GlcNAc-mediated inhibition of GSK-3β activity, which in turn promotes HSF1 activation and subsequent HSP expression.
  • These findings highlight O-GlcNAc as a key regulator of cellular stress tolerance through the modulation of the GSK-3β/HSF1 pathway.

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