Physical and functional interactions between hnRNP K and PRMT family proteins

Chan, James Yi Hsin; Hsieh, Tsai Yuan; Liu, Shu Ting; Chou, Wei-Yuan; Chung, Min Huey; Huang, Shih Ming

doi:10.1016/j.febslet.2008.12.025

Cited by 13 publications

(9 citation statements)

References 23 publications

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“…Our results suggest that hnRNP A2 functions as a transcriptional coactivator by associating with enhanceosomes through protein-protein interactions with its N-terminal RNA binding domains. In support of our model, a recent study showed that another member of the hnRNP protein family, hnRNP K, also functions as a transcriptional activator (Moumen et al, 2005;Chan et al, 2009;Yuan et al, 2009). However, hnRNP A2 functions in a distinctly different manner than hnRNP K, which has DNA binding properties (Tomonaga and Levens, 1995).…”

Section: Discussionsupporting

confidence: 81%

Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Guha

Pan

Fang

et al. 2009

MBoC

100

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Mitochondrial dysfunction and altered transmembrane potential initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a wide spectrum of cells. The mitochondrial stress response activates calcineurin, which regulates transcription factors, including a new nuclear factor-B (NF-B) pathway, different from the canonical and noncanonical pathways. In this study using a combination of small interfering RNA-mediated mRNA knock down, transcriptional analysis, and chromatin immunoprecipitation, we report a common mechanism for the regulation of previously established stress response genes Cathepsin L, RyR1, and Glut4. Stress-regulated transcription involves the cooperative interplay between NF-B (cRel: p50), C/EBP␦, cAMP response element-binding protein, and nuclear factor of activated T cells. We show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein (hnRNP) A2 as a coactivator. HnRNP A2 associates with the enhanceosome, mostly through protein-protein interactions with DNA-bound factors. Silencing of hnRNP A2 as well as other DNA binding signature factors prevents stress-induced transcriptional activation and reverses the invasiveness of mitochondrial DNA-depleted C2C12 cells. Induction of mitochondrial stress signaling by electron transfer chain inhibitors also involved hnRNPA2 activation. We describe a common mechanism of mitochondrial respiratory stress-induced activation of nuclear target genes that involves hnRNP A2 as a transcription coactivator. INTRODUCTIONMitochondrial biogenesis requires a coordinated interplay between proteins encoded by the nuclear and mitochondrial genomes. At least two different mechanisms have been described for the intergenomic cross-talk between these spatially separated genetic systems: anterograde and retrograde signaling (Liao et al., 1991;Liu and Butow, 2006). The anterograde intergenomic regulatory circuit involves nonmitochondrial signals that activate nuclear transcription factors to regulate both nuclear and mitochondrial gene expression (Poyton and McEwen, 1996;Kelly and Scarpulla, 2004;Spiegelman, 2007). The role of peroxisome proliferator-activated receptor ␥ coactivator-1 family of coactivator proteins in mitochondrial biogenesis and respiration is an example of this type of regulation (Puigserver et al., 1998). Regulation of cellular respiration by reduced mammalian target of rapamycin signaling probably represents another example of anterograde signaling (Bonawitz et al., 2007). In contrast, the retrograde intergenomic regulatory circuit involves the regulation of nuclear gene expression by mitochondrial stress signals that are initiated by metabolic stress, respiratory changes, or mitochondrial DNA damage (Liao and Butow, 1993;Jia et al., 1997;Biswas et al., 1999;Liu et al., 2001;Amuthan et al., 2002;Butow and Avadhani, 2004;Liu and Butow, 2006).The mammalian retrograde pathway is initiated by disruption of mitochondrial membrane potential (⌬⌿ m ), which can ...

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Section: Discussionsupporting

confidence: 81%

Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Guha

Pan

Fang

et al. 2009

MBoC

100

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“…Immunoprecipitation and in vivo reporter assays suggest a modulating function of hnRNP K methylation on p53 co-activator activity (Chen et al, 2008;Chan et al, 2009 (Gross et al, 2012). The interaction domains of both proteins bear asymmetrically dimethylated arginines.…”

Section: Introductionmentioning

confidence: 99%

Biophysical and biochemical analysis of hnRNP K: arginine methylation, reversible aggregation and combinatorial binding to nucleic acids

Moritz

Lilie

Vries

et al. 2014

Biological Chemistry

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Analysis of arginine methylation, which affects specific protein interactions in eukaryotic cells, requires access to methylated protein for biophysical and biochemical studies. Methylation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) upon co-expression with protein arginine methyltransferase 1 in E. coli was monitored by mass spectrometry and found to be identical to the modification of hnRNP K purified from mammalian cells. Recombinant non-methylated and arginine-methylated hnRNP K ( Met hnRNP K) were used to characterize self-aggregation and nucleic acid binding. Analytical ultracentrifugation and static light scattering experiments revealed that hnRNP K methylation does not impact reversible self-aggregation, which can be prevented by high ionic strength and organic additives. Filter binding assays were used to compare the binding of non-methylated and Met hn-RNP K to the pyrimidine repeat-containing differentiation control element (DICE) of reticulocyte 15-lipoxygenase mRNA 3′ UTR. No affinity differences were detected for both hnRNP K variants. A series of oligonucleotides carrying various numbers of C 4 motifs at different positions was used in steady state competition assays with fluorescently-labeled functional differentiation control element (2R). Quantitative evaluation indicated that all hnRNP K homology domains of hnRNP K contribute differentially to RNA binding, with KH1-KH2 acting as a tandem domain and KH3 as an individual binding domain.

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“…As shown in Figure 3B, the hnRNP K-specific as well as the ADMA-specific antibody clearly precipitated hnRNP K from the E. coli extract confirming the reactivity of the ADMA-specific antibody with hnRNP K in the absence of other eukaryotic proteins. Furthermore, we excluded binding to PRMT1 which is complexed to hnRNP K [29], [40] (data not shown). We also observed binding of a small fraction of hnRNP K by the NMA-antibody.…”

Section: Resultsmentioning

confidence: 99%

Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression

et al. 2012

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The Epstein-Barr Virus (EBV) -encoded EBNA2 protein, which is essential for the in vitro transformation of B-lymphocytes, interferes with cellular processes by binding to proteins via conserved sequence motifs. Its Arginine-Glycine (RG) repeat element contains either symmetrically or asymmetrically di-methylated arginine residues (SDMA and ADMA, respectively). EBNA2 binds via its SDMA-modified RG-repeat to the survival motor neurons protein (SMN) and via the ADMA-RG-repeat to the NP9 protein of the human endogenous retrovirus K (HERV-K (HML-2) Type 1). The hypothesis of this work was that the methylated RG-repeat mimics an epitope shared with cellular proteins that is used for interaction with target structures. With monoclonal antibodies against the modified RG-repeat, we indeed identified cellular homologues that apparently have the same surface structure as methylated EBNA2. With the SDMA-specific antibodies, we precipitated the Sm protein D3 (SmD3) which, like EBNA2, binds via its SDMA-modified RG-repeat to SMN. With the ADMA-specific antibodies, we precipitated the heterogeneous ribonucleoprotein K (hnRNP K). Specific binding of the ADMA- antibody to hnRNP K was demonstrated using E. coli expressed/ADMA-methylated hnRNP K. In addition, we show that EBNA2 and hnRNP K form a complex in EBV- infected B-cells. Finally, hnRNP K, when co-expressed with EBNA2, strongly enhances viral latent membrane protein 2A (LMP2A) expression by an unknown mechanism as we did not detect a direct association of hnRNP K with DNA-bound EBNA2 in gel shift experiments. Our data support the notion that the methylated surface of EBNA2 mimics the surface structure of cellular proteins to interfere with or co-opt their functional properties.

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Physical and functional interactions between hnRNP K and PRMT family proteins

Cited by 13 publications

References 23 publications

Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Biophysical and biochemical analysis of hnRNP K: arginine methylation, reversible aggregation and combinatorial binding to nucleic acids

Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression

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