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

被引：213

作者：

Levy, Dan ^{[1
]}

Kuo, Alex J. ^{[1
]}

Chang, Yanqi ^{[2
]}

Schaefer, Uwe ^{[3
]}

Kitson, Christopher ^{[4
]}

Cheung, Peggie ^{[1
]}

Espejo, Alexsandra ^{[5
]}

Zee, Barry M. ^{[6
]}

Liu, Chih Long ^{[1
,7
]}

Tangsombatvisit, Stephanie ^{[7
]}

Tennen, Ruth I. ^{[8
]}

Kuo, Andrew Y. ^{[1
]}

Tanjing, Song ^{[9
]}

Cheung, Regina ^{[7
]}

Chua, Katrin F. ^{[8
,10
]}

Utz, Paul J. ^{[7
]}

Shi, Xiaobing ^{[9
]}

Prinjha, Rab K. ^{[4
]}

Lee, Kevin ^{[4
]}

Garcia, Benjamin A. ^{[6
]}

Bedford, Mark T. ^{[5
]}

Tarakhovsky, Alexander ^{[3
]}

Cheng, Xiaodong ^{[2
]}

Gozani, Or ^{[1
]}

机构：

[1] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[2] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

[3] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10021 USA

[4] GlaxoSmithKline, EpiNova DPU, Immunoinflammat Grp, Stevenage, Herts, England

[5] MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA

[6] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[7] Stanford Univ, Dept Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA

[8] Stanford Univ, Sch Med, Dept Endocrinol Gerontol & Metab Med, Stanford, CA 94305 USA

[9] Univ Texas MD Anderson, Ctr Canc Epigenet, Houston, TX USA

[10] VA Palo Alto Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Palo Alto, CA USA

来源：

NATURE IMMUNOLOGY | 2011年 / 12卷 / 01期

基金：

美国国家卫生研究院;

关键词：

EXPRESSION PROFILES; ZETA-PKC; COMPLEXES; PROTEIN; G9A; PHOSPHORYLATION; INFLAMMATION; MECHANISM; BINDING;

D O I：

10.1038/ni.1968

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B 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-kappa B-activation-linked phosphorylation of RelA at Ser311 by protein kinase C-zeta (PKC-zeta) 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.

引用

页码：29 / U47

页数：11

共 48 条

[1] Mechanism of rapid transcriptional induction of tumor necrosis factor alpha-responsive genes by NF-κB [J].