Regulation of NF-κB activity through lysine monomethylation of p65

Kwee, Chee; Baltimore, David

doi:10.1073/pnas.0910439106

Cited by 202 publications

(202 citation statements)

References 25 publications

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“…The RelA L1 loop, which is critical for nucleotide sequence recognition and binding, has been shown to be monomethylated at K37 by SET7/9 (12) and symmetrically dimethylated at R30 by PRMT5 (16). These modifications cause an increase in the RelA affinity to DNA and activate NF-κB, in contrast with the inhibitory asymmetric R30 dimethylation by PRMT1 identified in our study.…”

Section: (7)contrasting

confidence: 55%

“…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).…”

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confidence: 99%

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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.

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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

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Section: (7)contrasting

confidence: 55%

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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.

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“…2B), and we have not yet analyzed the methylation status of all of the lysine residues of p65 by MS. In addition to the methylation of K314/K315 discussed above (25), a recent report shows that K37 of p65 is also monomethylated by SET9 (29). Therefore, the possibility of additional methylation sites on p65 should be investigated in the future, as should the possibility that the p50 subunit may also be methylated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Lü

Jackson²,

Wang

et al. 2009

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

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NF-κB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-κB regulatory pathway that is driven by reversible lysine methylation of the p65 subunit, carried out by a lysine methylase, the nuclear receptorbinding SET domain-containing protein 1 (NSD1), and a lysine demethylase, F-box and leucine-rich repeat protein 11 (FBXL11). Overexpression of FBXL11 inhibits NF-κB activity, and a high level of NSD1 activates NF-κB and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-κB activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-κB. Overexpression of FBXL11 slowed the growth of HT29 cancer cells, whereas shRNA-mediated knockdown had the opposite effect, and these phenotypes were dependent on K218/K221 methylation. In mouse embryo fibroblasts, the activation of most p65-dependent genes relied on K218/K221 methylation. Importantly, expression of the FBXL11 gene is driven by NF-κB, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-κB is an important element in the complex regulation of this key transcription factor. [RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52)], the p65/p50 heterodimer functions most often in the "classical" signaling pathway (1). Constitutive NF-κB activation is frequently associated with a number of pathological conditions, including inflammation and cancer, and is well known to be involved in tumor angiogenesis and invasiveness (2). Loss of the normal regulation of NF-κB is a major contributor to the deregulated growth, resistance to apoptosis, and propensity to metastasize observed in many different cancers (3). Our data, showing NF-κB activation in many cancer-derived cell lines (4, 5), further support the strong correlation between constitutive NF-κB activation and cancer. Thus, understanding the complexity of NF-κB-dependent signaling is an important aspect of dealing with these diseases.NF-κB has a variety of functions and is regulated by hundreds of different stimuli in different cell types (6). Specialized control of NF-κB activity is critical for achieving its normal transient activation in response to stress. Regardless of the stimulus, all pathways leading to NF-κB activation depend on inducing posttranslational modifications of the IκB kinase, IκB proteins, or NF-κB subunits. These regulatory modifications, including phosphorylation, ubiquitination, acetylation, sumolation, and nitrosylation, vary depending on the specific stimulus and context (7).We have developed a lentiviral validation-based insertional (VBIM) method to create mutant cell lines in which the overexpression of specific cellular proteins, driven by inserted CMV promoters, is responsible for altered phenotypes. We used this method to identify the F-box and leucine-rich repeat protein 11 (FBXL11) as a potent negative regulator of NF-κB and to show that its demethylase activity was required for this function (8). FBXL11, previous...

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“…4,5 However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3, 13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear.…”

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confidence: 99%

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

et al. 2014

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During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity. Cell Death and Differentiation (2014) 21, 1889-1899; doi:10.1038/cdd.2014.108; published online 15 August 2014Lysine methylation of non-histone proteins has recently emerged as a novel regulatory mechanism to control protein functions. 1-4Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) is a founding member of the family of non-chromatin lysine methyltransferases (KMTases). Set7/9 was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro. 4,5However, we and others showed that the recombinant Set7/9 failed to target nucleosomes for methylation, [6][7][8] suggesting that Set7/9 functions as a factor-specific KMTase. There have been several non-histone proteins reported as the substrates for Set7/9, including TAF10 (TATA box binding protein (TBP)-associated factor, 30 kDa), 9 oestrogen receptor a (ERa), 10 RelA, 11 PCAF (P300/CBP-associated factor), 12 Stat3,13 Yap, 14 and Suv39h1. 15 However, in most cases the functional significance of this methylation is still not clear. The beststudied targets of Set7/9-mediated methylation are p53 16 and E2 promoter-binding factor 1 (E2F1), 17 transcription factors involved in regulation of DNA damage response (DDR).In response to genotoxic stress cancer cells undergo cell-cycle arrest either in G1/S or G2/M or in both checkpoints. The presence of intact p53 in cancer cells mediates transient G1/S checkpoint arrest, 18,19 which allows cells to repair the damaged DNA before replication or, if the amount of damage is insurmountable, drives cells into apoptosis. 20,21On the contrary, the activity of the E2F family transcription factors, especially E2F1, drives cells from the G1/S block to mitosis. 22,23 Transcriptional activity of E2F1, in turn, is repressed by the retin...

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Regulation of NF-κB activity through lysine monomethylation of p65

Cited by 202 publications

References 25 publications

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

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

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

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