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.
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.
Department of Biology, Stanford University, Stanford, California, USA.
Dan
D
Levy
Alex J
AJ
Kuo
Yanqi
Y
Chang
Uwe
U
Schaefer
Christopher
C
Kitson
Peggie
P
Cheung
Alexsandra
A
Espejo
Barry M
BM
Zee
Chih Long
CL
Liu
Stephanie
S
Tangsombatvisit
Ruth I
RI
Tennen
Andrew Y
AY
Kuo
Song
S
Tanjing
Regina
R
Cheung
Katrin F
KF
Chua
Paul J
PJ
Utz
Xiaobing
X
Shi
Rab K
RK
Prinjha
Kevin
K
Lee
Benjamin A
BA
Garcia
Mark T
MT
Bedford
Alexander
A
Tarakhovsky
Xiaodong
X
Cheng
Or
O
Gozani
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D019175:DNA Methylation; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008239:Lysine / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D011496:Protein Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D006657:Histones; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; C455847:EHMT1 protein, human; D011496:Protein Methyltransferases; C562071:SETD6 protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine