Abstract
NF-kappaB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-kappaB regulatory pathway that is driven by reversible lysine methylation of the p65 subunit, carried out by a lysine methylase, the nuclear receptor-binding SET domain-containing protein 1 (NSD1), and a lysine demethylase, F-box and leucine-rich repeat protein 11 (FBXL11). Overexpression of FBXL11 inhibits NF-kappaB activity, and a high level of NSD1 activates NF-kappaB and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-kappaB activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-kappaB. Overexpression of FBXL11 slowed the growth of HT29 cancer cells, whereas shRNA-mediated knockdown had the opposite effect, and these phenotypes were dependent on K218/K221 methylation. In mouse embryo fibroblasts, the activation of most p65-dependent genes relied on K218/K221 methylation. Importantly, expression of the FBXL11 gene is driven by NF-kappaB, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-kappaB is an important element in the complex regulation of this key transcription factor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Cells, Cultured
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Cytokines / metabolism
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Embryo, Mammalian / cytology
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Fibroblasts / cytology
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Fibroblasts / physiology
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Gene Expression Regulation
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Lysine / metabolism*
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Methylation
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxidoreductases, N-Demethylating
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Protein Methyltransferases / genetics
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Protein Methyltransferases / metabolism
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
Substances
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Cytokines
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F-Box Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Protein Subunits
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Transcription Factor RelA
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FBXL11 protein, mouse
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM2A protein, human
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Oxidoreductases, N-Demethylating
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Histone Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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NSD1 protein, human
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Lysine