PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65

Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen; Byun, Hee Sun; Jeon, Joonryong; Lee, Yoonjung; Hong, Jang Hee; Kim, Jin Man; Huang, Song; Choi, Seung Won; Kim, Seon Hwan; Sohn, Kyung Cheol; Ro, Hyunju; Lee, Jihoon; Lü, Tao; Stark, George R.; Shen, Han‐Ming; Liu, Zheng Gang; Park, Jongsun; Hur, Gang Min

doi:10.1038/ncomms3062

Cited by 51 publications

(48 citation statements)

References 45 publications

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“…Remarkably, expression of the FBXL11 gene is induced in response to NF-κB activation, forming a unique negative feedback loop similar in effect to the one that involves the well-known negative regulator IκB (5). Recently, the Hur group (20) reported that glioma-expressed antigen 2 (PHF20) interacts with p65 by recognizing methylation at K218 and K221. This methylation-dependent interaction of PHF20 with p65 leads to persistent NF-κB phosphorylation and function by limiting the recruitment of protein phosphatase PP2A to p65 (20).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the Hur group (20) reported that glioma-expressed antigen 2 (PHF20) interacts with p65 by recognizing methylation at K218 and K221. This methylation-dependent interaction of PHF20 with p65 leads to persistent NF-κB phosphorylation and function by limiting the recruitment of protein phosphatase PP2A to p65 (20). Yang et al (6) reported that K314 and K315 of p65 are monomethylated by SET7/9 in response to NF-κB activation, an inhibitory modification that stimulates proteosome-mediated degradation of promoter-associated p65.…”

Section: Discussionmentioning

confidence: 99%

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PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Wang

Miyagi

et al. 2013

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

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The ubiquitous inducible transcription factor NF-κB plays central roles in immune and inflammatory responses and in tumorigenesis. Complex posttranslational modifications of the p65 subunit (RelA) are a major aspect of the extremely flexible regulation of NF-κB activity. Although phosphorylation, acetylation, ubiquitination, and lysine methylation of NF-κB have been well described, arginine methylation has not yet been found. We now report that, in response to IL-1β, the p65 subunit of NF-κB is dimethylated on arginine 30 (R30) by protein-arginine methyltransferase 5 (PRMT5). Expression of the R30A and R30K mutants of p65 substantially decreased the ability of NF-κB to bind to κB elements and to drive gene expression. A model in which dimethyl R30 is placed into the crystal structure of p65 predicts new van der Waals contacts that stabilize intraprotein interactions and indirectly increase the affinity of p65 for DNA. PRMT5 was the only arginine methyltransferase that coprecipitated with p65, and its overexpression increased NF-κB activity, whereas PRMT5 knockdown had the opposite effect. Microarray analysis revealed that ∼85% of the NF-κB-inducible genes that are down-regulated by the R30A mutation are similarly down-regulated by knocking PRMT5 down. Many cytokine and chemokine genes are among these, and conditioned media from cells expressing the R30A mutant of p65 had much less NF-κB-inducing activity than media from cells expressing the wild-type protein. PRMT5 is overexpressed in many types of cancer, often to a striking degree, indicating that high levels of this enzyme may promote tumorigenesis, at least in part by facilitating NF-κB-induced gene expression.histone | mass spectrometry T he NF-κB family is comprised of two protein subfamilies: c-Rel, RelB, and RelA (p65), which include transactivation domains in their C termini, and p100 (p52) and p105 (p50), which include a number of ankyrin repeats in their C termini and have transrepressive functions. All family members include an N-terminal DNA-binding region, the Rel homology domain (1). In the absence of an activating stimulus, NF-κB is located in the cytoplasm in a complex with the inhibitory IκB protein. In the classic pathway of NF-κB activation, extracellular signals activate IκB kinase, which phosphorylates IκBα, leading to its ubiquitination and degradation by proteasomes. NF-κB, liberated from IκB, translocates to the nucleus to regulate its target genes (2). The NF-κB pathway is regulated by means of several different posttranslational modifications, including ubiquitination, phosphorylation, acetylation, sumoylation, and nitrosylation (3). The recent work of several laboratories has revealed the reversible methylation of nonhistone proteins by enzymes that were discovered on the basis of their activities toward histones. For NF-κB, we found that in response to an activating signal, such as treatment with IL-1β, the p65 subunit is reversibly methylated on two specific lysine residues by chromatin remodeling enzymes in ways that profoundly aff...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Wang

Miyagi

et al. 2013

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

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221

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“…The activating monomethylation of K218 and di-methylation of K221 are both catalyzed by the H3K36 methyltransferase nuclear receptorbinding SET domain-containing protein (NSD1) and the methyl groups can be removed, leading to loss of NF-κB function, by the H3K36 demethylase FBXL11. Recently, the Hur group (16) reported that glioma-expressed antigen 2 (PHF20) interacts with p65 by recognizing methylation at K218 and K221. This methylation-dependent interaction of PHF20 with p65 leads to persistent NF-κB phosphorylation and function by limiting the recruitment of protein phosphatase PP2A to p65 (16).…”

mentioning

confidence: 99%

“…Recently, the Hur group (16) reported that glioma-expressed antigen 2 (PHF20) interacts with p65 by recognizing methylation at K218 and K221. This methylation-dependent interaction of PHF20 with p65 leads to persistent NF-κB phosphorylation and function by limiting the recruitment of protein phosphatase PP2A to p65 (16). This important observation further confirms the biological importance of lysine methylation of p65.…”

mentioning

confidence: 99%

Role of lysine methylation of NF-κB in differential gene regulation

Lü

Yang

Huang

et al. 2013

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

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Lysine methylation of the p65 subunit of nuclear factor κB (NF-κB) on K218 and K221 together or K37 alone strongly enhances gene expression in response to cytokines. We analyzed the effects of Kto-Q mutations in the REL homology domain of p65 on the response to IL-1β in 293 cells with low levels of p65. The K218/ 221Q mutation greatly reduced the expression of 39 of 82 genes, whereas the K37Q mutation reduced the expression of 23 different genes. Enhanced expression of the lysine demethylase FBXL11, which catalyzes the demethylation of K218 and K221 specifically, inhibited the expression of most of the genes that were inhibited by the DKQ mutation. CHIP-Seq analysis showed that the K218/ 221Q mutation greatly reduces the affinity of p65 for many promoters and that the K37Q mutation does not. Structural modeling showed that the newly introduced methyl groups of K218 and K221 interact directly with DNA to increase the affinity of p65 for specific κB sites. Thus, the K218/221Q and K37Q mutations have dramatically different effects because methylations of these residues affect different genes by distinct mechanisms.protein methylation | histone modifying enzyme M embers of the nuclear factor κB (NF-κB) family are central coordinators of innate and adaptive immune responses. Of the five family members in mammals [RelA (p65), RelB, c-Rel, NF-κB 1 (p50), and NF-κB2 (p52)], the p65/p50 heterodimer functions most often, in the "classic" signaling pathway (1). In unstimulated cells, NF-κB dimers are retained in an inactive state in the cytoplasm through binding to a member of the Inhibitor of κB (IκB) family. Activation of NF-κB is catalyzed by IκB kinase (IKK), followed by the phosphorylation and degradation of IκB, the phosphorylation of NF-κB itself, and the liberation of phosphorylated NF-κB dimers, which translocate to the nucleus and activate the transcription of target genes (2). The p65 subunit of NF-κB can be phosphorylated on more than a dozen different serine and threonine residues in response to activating stimuli, leading to differential gene regulation and dependent biological effects. Mutation of these phosphorylation sites modulates activity, affecting the ability of p65 to transactivate some promoters, but leaving others essentially unaffected (3). It seems likely that additional posttranslational modifications of p65 also occur in a signal-dependent manner, and that differential posttranslational modifications of p65 are likely to be responsible for the differences in p65 function that have been observed in response to different activating stimuli (4). The activity of NF-κB is regulated by many different stimuli in all cell types, with many different functional consequences (4). Regardless of the stimulus, all pathways leading to NF-κB activation involve posttranslational modifications of IKK, IκB, and NF-κB itself, including phosphorylation, ubiquitination, acetylation, sumoylation, and nitrosylation, and the specific modifications that occur depend on the nature of the inducing stimulus (5). Recent dis...

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“…The methylation of p65 blocks recruitment of PP2A to p65, thereby leading to the persistent phosphorylation of p65 [34]. By using the immunohistochemistry (IHC) staining method, the authors showed that PHF20 and phosphorylated p65 are localized in the nucleus in glioma tissue specimens.…”

Section: Lysine Methylation Of P65mentioning

confidence: 99%

Methylation of NF-κB and its Role in Gene Regulation

Wang¹,

Prabhu²,

Hartley³

et al. 2018

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

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The nuclear factor κB (NF-κB) is one of the most pivotal transcription factors in mammalian cells. In many pathologies NF-κB is activated abnormally. This contributes to the development of various disorders such as cancer, acute kidney injury, lung disease, chronic inflammatory diseases, cardiovascular disease, and diabetes. This book chapter focuses on how methylation of NF-κB regulates its target genes differentially. The knowledge from this chapter will provide scientific strategies for innovative therapeutic intervention of NF-κB in a wide range of diseases.

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PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65

Cited by 51 publications

References 45 publications

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Role of lysine methylation of NF-κB in differential gene regulation

Methylation of NF-κB and its Role in Gene Regulation

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