Signal-dependent Control of Gluconeogenic Key Enzyme Genes through Coactivator-associated Arginine Methyltransferase 1

Krones-Herzig, Anja; Mesaros, Andrea; Metzger, Dagmar; Ziegler, Anja; Lemke, Ulrike; Herzig, Stephan

doi:10.1074/jbc.m509770200

Cited by 36 publications

(32 citation statements)

References 42 publications

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“…In addition to effects of PRMT5, the type I PRMT family member PRMT4/coactivator-associated arginine methyltransferase 1 (CARM1) has also been found to promote gluconeogenic gene expression via an interaction with CREB and through subsequent increases in H3 methylation (15). Indeed, we have also detected increases in asymmetric H3R8me2 amounts at CREBbinding sites, potentially catalyzed by the type I enzyme PRMT2, in response to glucagon simulation.…”

Section: Discussionsupporting

confidence: 54%

PRMT5 modulates the metabolic response to fasting signals

Tsai

Niessen

Goebel

et al. 2013

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

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Under fasting conditions, increases in circulating glucagon maintain glucose balance by promoting hepatic gluconeogenesis. Triggering of the cAMP pathway stimulates gluconeogenic gene expression through the PKA-mediated phosphorylation of the cAMP response element binding (CREB) protein and via the dephosphorylation of the latent cytoplasmic CREB regulated transcriptional coactivator 2 (CRTC2). CREB and CRTC2 activities are increased in insulin resistance, in which they promote hyperglycemia because of constitutive induction of the gluconeogenic program. The extent to which CREB and CRTC2 are coordinately up-regulated in response to glucagon, however, remains unclear. Here we show that, following its activation, CRTC2 enhances CREB phosphorylation through an association with the protein arginine methyltransferase 5 (PRMT5). In turn, PRMT5 was found to stimulate CREB phosphorylation via increases in histone H3 Arg2 methylation that enhanced chromatin accessibility at gluconeogenic promoters. Because depletion of PRMT5 lowers hepatic glucose production and gluconeogenic gene expression, these results demonstrate how a chromatin-modifying enzyme regulates a metabolic program through epigenetic changes that impact the phosphorylation of a transcription factor in response to hormonal stimuli.

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Section: Discussionsupporting

confidence: 54%

PRMT5 modulates the metabolic response to fasting signals

Tsai

Niessen

Goebel

et al. 2013

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

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“…The methyltransferase PRMT1 is known to increase activity of transcription factors involved in glucose homeostasis (13)(14)(15). Whereas previous results have implicated CARM1 (PRMT4) in the regulation of G6PC (16), the present study found that knockdown of PRMT1 reduced G6PC expression, suggesting that PRMT1 also participates in the transcriptional regulation of this gluconeogenic gene. This strengthens the association between ADMA-producing co-activators and gluconeogenic enzyme expression.…”

Section: Discussioncontrasting

confidence: 51%

“…SAM and SAH levels as well as protein-arginine methylation are altered in diabetic models (5-9) and in humans (10, 11). Gluconeogenic enzyme expression, responsible for hepatic glucose production and hyperglycemia in diabetics, is dependent upon methyltransferases (16). Human subjects with insulin resistance and non-alcoholic steatohepatitis have reduced capacity for transmethylation of methionine (11), and the capacity for methylation is related to insulin resistance and metabolic syndrome (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

S-Adenosylmethionine-dependent Protein Methylation Is Required for Expression of Selenoprotein P and Gluconeogenic Enzymes in HepG2 Human Hepatocytes

Jackson

Cao

Zeng

et al. 2012

Journal of Biological Chemistry

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Background: Protein methylation is required for gluconeogenic enzyme expression. Selenoprotein P is transcriptionally controlled similarly to gluconeogenenic enzymes. S-adenosylhomocysteine is an inhibitor of methylation. Results: S-Adenosylhomocysteine decreases selenoprotein P and gluconeogenic enzyme expression. Conclusion: Hepatocellular methylation is a nexus of control over selenoprotein P and gluconeogenic enzyme expression. Significance: Determination of how methylation affects proteins involved in type II diabetes may aid in development of therapeutics.

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“…A few studies have implicated CARM1 as a regulator of cellular metabolism [5,[66][67][68][69]. CARM1 was shown to be a co-activator of PPARγ [5], a key transcription factor regulating glucose and lipid metabolism.…”

Section: Carm1 O-glcnacylation May Be a Sensor Of Cellular Stress Andmentioning

confidence: 99%

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

Charoensuksai

Kühn

Wang

et al. 2015

Biochemical Journal

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Co-activator-associated arginine methyltransferase 1 (CARM1) asymmetrically di-methylates proteins on arginine residues. CARM1 was previously known to be modified through O-linked-β-N-acetylglucosaminidation (O-GlcNAcylation). However, the site(s) of O-GlcNAcylation were not mapped and the effects of O-GlcNAcylation on biological functions of CARM1 were undetermined. In the present study, we describe the comprehensive mapping of CARM1 post-translational modification (PTM) using top-down MS. We found that all detectable recombinant CARM1 expressed in human embryonic kidney (HEK293T) cells is automethylated as we previously reported and that about 50% of this automethylated CARM1 contains a single O-linked-β-N-acetylglucosamine (O-GlcNAc) moiety [31]. The O-GlcNAc moiety was mapped by MS to four possible sites (Ser595, Ser598, Thr601 and Thr603) in the C-terminus of CARM1. Mutation of all four sites [CARM1 quadruple mutant (CARM1QM)] markedly decreased O-GlcNAcylation, but did not affect protein stability, dimerization or cellular localization of CARM1. Moreover, CARM1QM elicits similar co-activator activity as CARM1 wild-type (CARM1WT) on a few transcription factors known to be activated by CARM1. However, O-GlcNAc-depleted CARM1 generated by wheat germ agglutinin (WGA) enrichment, O-GlcNAcase (OGA) treatment and mutation of putative O-GlcNAcylation sites displays different substrate specificity from that of CARM1WT. Our findings suggest that O-GlcNAcylation of CARM1 at its C-terminus is an important determinant for CARM1 substrate specificity.

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Signal-dependent Control of Gluconeogenic Key Enzyme Genes through Coactivator-associated Arginine Methyltransferase 1

Cited by 36 publications

References 42 publications

PRMT5 modulates the metabolic response to fasting signals

PRMT5 modulates the metabolic response to fasting signals

S-Adenosylmethionine-dependent Protein Methylation Is Required for Expression of Selenoprotein P and Gluconeogenic Enzymes in HepG2 Human Hepatocytes

O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity

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