HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Bandyopadhyay, Smarajit; Harris, Daniel P.; Adams, Gregory N.; Lausé, Gregory E.; McHugh, Anne; Tillmaand, Emily G.; Money, Angela; Willard, Belinda; Fox, Paul L.; DiCorleto, Paul E.

doi:10.1128/mcb.05977-11

Cited by 77 publications

(55 citation statements)

References 68 publications

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“…Inhibition of arginine methylation of EBNA1 altered its localization, resulting in the formation of EBNA1 rings around nucleoli (27). Another example is the homeobox transcription factor HOXA9, which is methylated on R140 by PRMT5, a modification that is essential for the expression of endothelial cell leukocyte adhesion molecules during the endothelial cell inflammatory response (28). PRMT5 has been recently shown to promote cell growth and transformation by other mechanisms.…”

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.

210

221

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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%

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

Wang

Miyagi

et al. 2013

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

210

221

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“…Western Blotting-Lysates were resolved on 10% bis-tris acrylamide gels (2). Proteins were transferred to PVDF membranes and blocked with 5% nonfat milk or protein-free blocking buffer (Pierce; catalog no.…”

Section: Methodsmentioning

confidence: 99%

“…Studies from our laboratory and others identify arginine methylation as a contributing factor in induction of the inflammatory genes E-selectin, VCAM-1, IL-2, CXCL8/IL-8, and IB␣ (2)(3)(4)(5). Arginine residues in mammalian proteins can carry zero, one, or two methyl groups on their terminal () nitrogen atoms.…”

Section: Activation Of Endothelial Cells (Ec)mentioning

confidence: 99%

Tumor Necrosis Factor (TNF)-α Induction of CXCL10 in Endothelial Cells Requires Protein Arginine Methyltransferase 5 (PRMT5)-mediated Nuclear Factor (NF)-κB p65 Methylation

Harris

Bandyopadhyay

Maxwell

et al. 2014

Journal of Biological Chemistry

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Background: NF-B post-translational modifications contribute to gene-specific transcriptional activation. Results: Symmetrical dimethylation of NF-B p65 by PRMT5 enhances CXCL10 induction in response to TNF-␣. Conclusion: Arginine methylation of p65 is a novel mechanism regulating inflammatory chemokine induction. Significance: Methylation of specific NF-B arginine residues contributes to promoter targeting and transcriptional activation.

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“…For example, methylation of histone protein by PRMT5 can regulate DNA damage repairing, gene expression, and RNA splicing (14). Methylation of non-histone proteins, such as p53, HOXA9, NF-B, and E2F-1, by PRMT5 has been implicated in the regulation of cell growth, apoptosis, and inflammation (15)(16)(17). PRMT5 is widely expressed in different human tissues, with high expression levels observed in heart, skeletal muscle, and testis (18,19).…”

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confidence: 99%

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

Chen

Sun

2014

Journal of Biological Chemistry

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Background: Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins. Results: PRMT5 interacts with and methylates GATA4 in cardiomyocytes. Conclusion: PRMT5 suppresses hypertrophic responses in cardiomyocytes by attenuating GATA4 transcriptional activity. Significance: Targeting PRMT5 may represent a novel therapeutic strategy for preventing cardiac hypertrophy and heart failure.

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HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Cited by 77 publications

References 68 publications

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

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

Tumor Necrosis Factor (TNF)-α Induction of CXCL10 in Endothelial Cells Requires Protein Arginine Methyltransferase 5 (PRMT5)-mediated Nuclear Factor (NF)-κB p65 Methylation

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

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