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

Levy, Dan; Kuo, Alex; Chang, Yanqi; Schaefer, Uwe; Kitson, Christopher; Cheung, Peggie; Espejo, Alexsandra; Zee, Barry M.; Liu, Chih Long; Tangsombatvisit, Stephanie; Tennen, Ruth I.; Kuo, Andrew; Song, Tanjing; Cheung, Regina; Chua, Katrin F.; Utz, Paul J.; Shi, Xiaobing; Prinjha, Rab K.; Lee, Kevin; Garcia, Benjamin A.; Bedford, Mark T.; Tarakhovsky, Alexander; Cheng, Xiaodong; Gozani, Or

doi:10.1038/ni.1968

Cited by 236 publications

(301 citation statements)

References 48 publications

Supporting

Mentioning

291

Contrasting

Order By: Relevance

“…It is well established that the NF-B pathway is regulated exceptionally tightly by several post-translational modifications, including phosphorylation, ubiquitination, acetylation, and methylation (11)(12)(13). However, it remains to be determined whether these modifications influence muscle function, size, or atrophy.…”

mentioning

confidence: 99%

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Lee

Goldberg

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

NF-B is best known for its pro-inflammatory and anti-apoptotic actions, but in skeletal muscle, NF-B activation is important for atrophy upon denervation or cancer. Here, we show that also upon fasting, NF-B becomes activated in muscle and is critical for the subsequent atrophy. Following food deprivation, the expression and acetylation of the p65 of NF-B on lysine 310 increase markedly in muscles. NF-B inhibition in mouse muscles by overexpression of the IB␣ superrepressor (IB␣-SR) or of p65 mutated at Lys-310 prevented atrophy. Knockdown of GCN5 with shRNA or a dominant-negative GCN5 or overexpression of SIRT1 decreased p65K310 acetylation and muscle wasting upon starvation. In addition to reducing atrogene expression, surprisingly inhibiting NF-B with IB␣-SR or by GCN5 knockdown in these muscles also enhanced AKT and mechanistic target of rapamycin (mTOR) activities, which also contributed to the reduction in atrophy. These new roles of NF-B and GCN5 in regulating muscle proteolysis and AKT/ mTOR signaling suggest novel approaches to combat muscle wasting.

show abstract

mentioning

confidence: 99%

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Lee

Goldberg

2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Methylation of RelA by SETD6 inhibits the transactivation activity of RelA (25). We detected RelA bound to the promoter of GnRH via ChIP in GT1-7 cells transfected with SETD6…”

Section: Significancementioning

confidence: 99%

“…4B). Ala360Glu is located in one of the α-helices of the C-terminal domain of the SETD6 protein (25,28), and the Glu residue is highly conserved from chickens to humans (Fig. 4C).…”

Section: Significancementioning

confidence: 99%

“…Hence, SETD6 (Ala360Glu) was the most promising causative SNP on chromosome 18. SETD6 catalyzes methylation of lysine residues in the RelA subunit of NF-κB (25), which is involved in the transcriptional regulation of GnRH (26). We compared the lysine methyltransferase activity of bovine SETD6 Ala and SETD6 Glu using immortalized murine hypothalamic neurons synthesizing GnRH, referred to as GT1-7 cells (27), when repressing endogenous setd6 by cotransfecting murine siSETD6.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Genetic variants related to gap junctions and hormone secretion influence conception rates in cows

Sugimoto

Sasaki

Gotoh³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The recent decline in fertility is a serious problem in the dairy industry. To overcome this problem, we performed a genome-wide association study using 384 Holsteins and identified four loci associated with conception rates. Two of them contained gap junctionrelated genes: PKP2 and CTTNBP2NL. Further analysis confirmed that PKP2 increased connexin 43, a gap junction protein, whereas CTTNBP2NL dephosphorylated connexin 43. Knockdown of PKP2 or overexpression of CTTNBP2NL inhibited embryo implantation in mice. The other two loci contained neuroendocrine-related genes: SETD6 and CACNB2. Additional experiments indicated that SETD6 is involved in the transcriptional regulation of gonadotropin-releasing hormone, whereas CACNB2 controlled the secretion of folliclestimulating hormone in cattle. The total allele substitution effect of these genes on conception rate was 3.5%. Our findings reveal important roles for gap junction communication and the neuroendocrine system in conception and suggest unique selection methods to improve reproductive performance in the livestock industry.

show abstract

“…Recent work of several laboratories has identified methylation as another regulatory RelA modification that controls gene expression downstream of TNFα and IL-1β signaling. Several histone lysine methyltransferases, including SET7/9, SETD6, and NSD1, have been shown to both positively and negatively regulate NF-κB through direct monomethylation or dimethylation of distinct lysine residues in RelA (12)(13)(14)(15). Recent studies also have shown that RelA is methylated by the type II protein arginine methyltransferase 5 (PRMT5), which catalyzes the synthesis of ω-N Gmonomethylarginine (MMA) and symmetric ω-N G ,N′ G -dimethylarginine (SDMA) (16,17).…”

mentioning

confidence: 99%

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Reintjes

Fuchs

Kremser

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB-activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA-NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.arginine methylation | genes | TNFα | NF-κB

show abstract

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

Cited by 236 publications

References 48 publications

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

Genetic variants related to gap junctions and hormone secretion influence conception rates in cows

Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response

Contact Info

Product

Resources

About