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Glutamine Induces Heat Shock Protein Expression Via O‐Glycosylation and Phosphorylation of HSF‐1 and Sp1
Author(s) -
Singleton Kristen D.,
Wischmeyer Paul E.
Publication year - 2008
Publication title -
journal of parenteral and enteral nutrition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.935
H-Index - 98
eISSN - 1941-2444
pISSN - 0148-6071
DOI - 10.1177/0148607108320661
Subject(s) - phosphorylation , hsp70 , glycosylation , glutamine , sepsis , chemistry , threonine , saline , heat shock protein , medicine , microbiology and biotechnology , serine , biology , biochemistry , amino acid , gene
Background: Glutamine (GLN) improves outcome in experimental and clinical states of illness and injury. The authors hypothesized GLN‐mediated enhancement of O‐glycosylation and subsequent phosphorylation of key transcription factors in the HSP70 pathway would lead to increased HSP70 expression following experimental sepsis. Methods: Mice underwent cecal ligation and puncture (CLP)–induced sepsis and were treated with GLN (0.75 g/kg) or a saline placebo 30 minutes after CLP. A separate group of mice was treated with mithramycin, an Sp1 inhibitor. Lung tissue was harvested at 1, 2, 6, and 24 hours after CLP and was analyzed for HSF‐1 and Sp1 O‐GlcNAc modification, α‐p‐threonine modification, and HSP70. Results: GLN increased O‐GlcNAc modification of HSF‐1 and Sp1 at 1 and 2 hours after sepsis ( P < .001 vs saline). Samples immunoprecipitated for Sp1 and probed for subsequent phosphorylation showed a significant increase in nuclear α‐p‐threonine‐modified Sp1 at 2 and 6 hours after sepsis ( P < .001 vs saline). GLN increased phosphorylated nuclear HSF‐1 at 1 and 2 hours after CLP ( P < .001). Finally, GLN treatment increased HSP70 4‐fold ( P < .01), but when treated with mithramycin, this increase was attenuated at 2, 6, and 24 hours ( P < .001 vs no mithramycin treatment). Conclusions: These results indicate that GLN induces HSF‐1 and Sp1, which is known to lead to their nuclear translocation. The molecular mechanism of GLN‐mediated HSP70 expression appears to be dependent on O‐GlcNAc pathway activation and subsequent O‐glycosylation and phosphorylation of key transcription factors required for HSP70 induction.