Aryl Hydrocarbon Receptor Activation by Dioxin Targets Phosphoenolpyruvate Carboxykinase (PEPCK) for ADP-ribosylation via 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible Poly(ADP-ribose) Polymerase (TiPARP)

• Published in: The Journal of biological chemistry Vol. 288; no. 30; pp. 21514 - 21525
• Main Authors: Diani-Moore, Silvia, Zhang, Sheng, Ram, Payal, Rifkind, Arleen B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-07-2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Diphosphate Ribose - metabolism; ADP-ribosylation; Amino Acid Sequence; Animals; Aryl Hydrocarbon Receptor; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Chick Embryo; Chickens; Dioxin; Enzymology; Gene Expression; HEK293 Cells; Hep G2 Cells; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Liver; Molecular Sequence Data; Phosphoenolpyruvate Carboxykinase; Phosphoenolpyruvate Carboxykinase (ATP) - genetics; Phosphoenolpyruvate Carboxykinase (ATP) - metabolism; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Polychlorinated Dibenzodioxins - pharmacology; Protein Processing, Post-Translational - drug effects; Proteomics; Rats; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Amino Acid; Tandem Mass Spectrometry; TiPARP; TiPARP; Aryl Hydrocarbon Receptor; Phosphoenolpyruvate Carboxykinase; Dioxin; Liver; ADP-ribosylation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.458067

Effects of the environmental toxin and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) include a wasting syndrome associated with decreased gluconeogenesis. TCDD is a potent activator of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The relationship between gene activation by the AHR and TCDD toxicities is not well understood. We recently identified a pathway by which the AHR target gene TiPARP (TCDD-inducible poly(ADP-ribose) polymerase) contributes to TCDD suppression of transcription of phosphoenolpyruvate carboxykinase (PEPCK), a key regulator of gluconeogenesis, by consuming NAD+ and decreasing Sirtuin 1 activation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a transcriptional activator of PEPCK. We report here that TCDD-induced TiPARP also targets PEPCK for ADP-ribosylation. Both cytosolic and mitochondrial forms of PEPCK were found to undergo ADP-ribosylation. Unexpectedly, AHR suppression also enhanced ADP-ribosylation and did so by a poly(ADP-ribose) polymerase-independent mechanism. This report 1) identifies ADP-ribosylation as a new posttranslational modification for PEPCK, 2) describes a pathway by which transcriptional induction of TiPARP by the AHR can lead to a downstream posttranslational change in a TCDD target protein (PEPCK), and 3) reveals that the AHR exerts complex, previously unidentified modulatory effects on ADP-ribosylation.
Background: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-activated aryl hydrocarbon receptor (AHR) decreases gluconeogenesis by suppressing phosphoenolpyruvate carboxykinase (PEPCK) transcription via TCDD-inducible poly(ADP-ribose)-polymerase (TiPARP).
Results: AHR enhances PEPCK ADP-ribosylation through TiPARP, and AHR suppression increases ADP-ribosylation PARP-independently.
Conclusion: ADP-ribosylation, a new PEPCK posttranslational modification, is subject to complex regulation by the AHR.
Significance: AHR gene activation leads to ADP-ribosylation of PEPCK with implications for energy metabolism beyond TCDD toxicity.