TY - JOUR
T1 - O-linked β-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3β-dependent manner
AU - Kazemi, Zahra
AU - Chang, Hana
AU - Haserodt, Sarah
AU - McKen, Cathrine
AU - Zachara, Natasha E.
PY - 2010/12/10
Y1 - 2010/12/10
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.131102
DO - 10.1074/jbc.M110.131102
M3 - Article
C2 - 20926391
AN - SCOPUS:78649894035
SN - 0021-9258
VL - 285
SP - 39096
EP - 39107
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 50
ER -