BMB Section Seminar: "TIPARP and mono-ADP-ribosylation negatively regulate AHR"
Professor Jason Matthews, Division of Molecular Nutrition, Department of Nutrition, Faculty of Medicine, University of Oslo
AHR activity is regulated by TIPARP. Rights reserved J. Matthews.
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxic effects of the environmental contaminant, dioxin. Dioxin causes a range of toxic responses in laboratory rodents, including steatohepatitis and a lethal wasting syndrome; though, the mechanisms are still unclear. In humans, AHR activation is associated with increased risk for diabetes. AHR regulates the expression of many genes including TCDD-inducible poly(ADP-ribose) polymerase (TIPARP/PARP7/ARTD14). TIPARP is a member of the PARP family of enzymes that use NAD+ as a substrate to catalyse the transfer of single units of ADP-ribose or long chains of ADP-ribose onto themselves and onto their protein substrates in processes referred to as mono- or poly-ADP-ribosylation, respectively. I will present our recent studies characterizing TIPARP activity and its role in AHR-dependent transcription and function. We have shown that TIPARP is mono-ADP-ribosyltransferase and as part of a negative feedback loop regulates AHR activity. Tiparp-/- and hepatocyte specific TiparpHep-/- mice show increased sensitivity to dioxin-induced gene expression, toxicity, steatohepatitis and lethality. The mono-ADP-ribosylase, MacroD1, reversed TIPARP-dependent ADP-ribosylation of AHR and the repressive effects of TIPARP on AHR activity. Collectively, these data reveal previously unidentified roles for TIPARP, MacroD1, and ADP-ribosylation in AHR-mediated steatohepatitis and lethality in response to dioxin, and implicate TIPARP and mono-ADP-ribosylation as key regulators of AHR-dependent transcription. On going work reveals that TIPARP also regulates the activity of other ligand activated transcription factors, in particular members of the nuclear receptor family, suggesting that TIPARP is a more general regulator of transcription factor activity.
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