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

Autor: Katrin F. Chua, Dan Levy, Alexander Tarakhovsky, Regina Cheung, Xiaodong Cheng, Yanqi Chang, Mark T. Bedford, Benjamin A. Garcia, Paul J. Utz, Andrew Kuo, Barry M. Zee, Rab K. Prinjha, Peggie Cheung, Ruth I. Tennen, Alexsandra Espejo, Or Gozani, Uwe Schaefer, Xiaobing Shi, Song Tanjing, Alex J. Kuo, Stephanie Tangsombatvisit, Christopher Kitson, Kevin Lee, Chih Long Liu
Rok vydání: 2010
Předmět:
Zdroj: Nature Immunology. 12:29-36
ISSN: 1529-2916
1529-2908
DOI: 10.1038/ni.1968
Popis: 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.
Databáze: OpenAIRE
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