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.

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.

• Authors: Dan Levy, Alex J Kuo, Yanqi Chang, Uwe Schaefer, Christopher Kitson, Peggie Cheung, Alexsandra Espejo, Barry M Zee, Chih Long Liu, Stephanie Tangsombatvisit, Ruth I Tennen, Andrew Y Kuo, Song Tanjing, Regina Cheung, Katrin F Chua, Paul J Utz, Xiaobing Shi, Rab K Prinjha, Kevin Lee, Benjamin A Garcia, Mark T Bedford, Alexander Tarakhovsky, Xiaodong Cheng, Or Gozani
• Journal: Nature immunology (Nat Immunol) Vol. 12 Issue 1 Pg. 29-36 (Jan 2011) ISSN: 1529-2916 [Electronic] United States
• PMID: 21131967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• NF-kappa B
• RELA protein, human
• RNA, Small Interfering
• Transcription Factor RelA
• EHMT1 protein, human
• Protein Methyltransferases
• SETD6 protein, human
• Histone-Lysine N-Methyltransferase
• Lysine

Topics

• Arthritis, Rheumatoid (genetics, immunology, 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, immunology, metabolism)
• Protein Binding (genetics)
• Protein Methyltransferases (genetics, immunology, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (genetics, immunology)
• Transcription Factor RelA (genetics, immunology, metabolism)