Negative regulation of NF-κB action by Set9-mediated lysine methylation of the RelA subunit
| Autor: | Mingxi Li, Acacia Lamb, Lin Feng Chen, Neil L. Kelleher, Xiao Dong Yang, Bo Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Transcriptional Activation
Methyltransferase Recombinant Fusion Proteins Transcription Factor RelA Molecular Sequence Data Biology Histone-Lysine N-Methyltransferase Methylation General Biochemistry Genetics and Molecular Biology Article chemistry.chemical_compound RNA interference Humans Amino Acid Sequence Protein Methyltransferases Promoter Regions Genetic Molecular Biology RELA General Immunology and Microbiology Tumor Necrosis Factor-alpha General Neuroscience Lysine NF-kappa B NF-κB Molecular biology Cell biology Protein Subunits chemistry Histone methyltransferase Histone Methyltransferases RNA Interference |
| Popis: | Proper regulation of NF-kappaB activity is critical to maintain and balance the inflammatory response. Inactivation of the NF-kappaB complex relies in part on the proteasome-mediated degradation of promoter-bound NF-kappaB, but the detailed molecular mechanism initiating this process remains elusive. Here, we show that the methylation of the RelA subunit of NF-kappaB has an important function in this process. Lysine methyltransferase Set9 physically associates with RelA in vitro and in vivo in response to TNF-alpha stimulation. Mutational and mass spectrometric analyses reveal that RelA is monomethylated by Set9 at lysine residues 314 and 315 in vitro and in vivo. Methylation of RelA inhibits NF-kappaB action by inducing the proteasome-mediated degradation of promoter-associated RelA. Depletion of Set9 by siRNA or mutation of the RelA methylation sites prolongs DNA binding of NF-kappaB and enhances TNF-alpha-induced expression of NF-kappaB target genes. Together, these findings unveil a novel mechanism by which methylation of RelA dictates the turnover of NF-kappaB and controls the NF-kappaB-mediated inflammatory response. |
| Databáze: | OpenAIRE |
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