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O‐GlcNAcylation inhibits NFκB activation in rat aortic smooth muscle cells through proteasome inhibition
Author(s) -
Wang Kai,
Xing Dongqi,
Ho ShiuhRong,
Zhang Yun,
Chen YiuFai,
Oparil Suzanne,
Paterson Andrew
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.775.7
Subject(s) - proteasome , inflammation , iκbα , cytosol , nf κb , serine , chemistry , microbiology and biotechnology , phosphorylation , proteasome inhibitor , biochemistry , threonine , biology , enzyme , signal transduction , immunology
O‐GlcNAcylation is a dynamic protein posttranslational modification that adds the monosaccharide N‐acetylglucosamine (GlcNAc) to specific serine or threonine residues on target proteins. We have found that O‐GlcNAc modification is an endogenous inhibitor of the proteasome, the primary cellular complex to degrade proteins. A crucial element of the vascular injury response is the activation of NFκB dependent inflammatory genes. NFκB interacts with IκBα in the cytosol and is activated by IκBα degradation, allowing NFκB to translocate into the nucleus to induce gene expression. In this study, we tested if O‐GlcNAc can inhibit NFκB mediated inflammation by blocking IκBα degradation through proteasome inhibition. Rat aortic smooth muscle cells (RASMCs) were treated with 5 mM glucosamine (GlcN) for 1, 2, 4, 6, 12 hrs. At 12 hrs of GlcN treatment, O‐GlcNAc was increased 2‐fold and IκBα level by 21% compared to vehicle control. GlcN pretreatment significantly inhibited TNF‐α induced degradation of IκBα. RASMCs were pretreated with 5 mM GlcN and then incubated with TNF‐α (10 ng/ml) for an additional 60 min, resulting in a 60% increase in IκBα levels after 12 hrs of GlcN treatment. A 32% decrease in proteasome activity was detected after 12 hrs GlcN treatment (Figure). This study indicated that the O‐GlcNAc might inhibit TNF‐α induced inflammatory response in RASMCs by blocking NFκB activation through proteasome inhibition.