1. Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling.
- Author
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Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, and Gozani O
- Subjects
- Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid metabolism, Chromatin Assembly and Disassembly genetics, DNA Methylation, HEK293 Cells, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Humans, Inflammation, Lysine metabolism, NF-kappa B genetics, NF-kappa B immunology, Protein Binding genetics, Protein Methyltransferases genetics, Protein Methyltransferases immunology, RNA, Small Interfering genetics, Signal Transduction genetics, Signal Transduction immunology, Transcription Factor RelA genetics, Transcription Factor RelA immunology, Arthritis, Rheumatoid immunology, NF-kappa B metabolism, Protein Methyltransferases metabolism, Transcription Factor RelA metabolism
- Abstract
Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation-linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.
- Published
- 2011
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