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BBB seminar: Jason Matthews

TIPARP and ADP-ribosylation regulate aryl hydrocarbon receptor activity and dioxin-induced steatohepatitis and lethality

Jason Matthews
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxic effects of environmental contaminants, such as dioxin. Dioxin causes a range of toxic responses, including steatohepatitis and a lethal wasting syndrome; though, the mechanisms are still unclear. AHR regulates the expression of many genes including TCDD-inducible poly(ADP-ribose) polymerase (TIPARP/PARP7). TIPARP is a member of the PARP family of enzymes that use NAD+ as a substrate to catalyze 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 discuss our recent studies characterizing TIPARP activity and its role in AHR-dependent transcription and function. We have shown that TIPARP is a mono-ADP-ribosyltransferase and as part of a negative feedback loop regulates AHR transcriptional activity. Tiparp-/- mice show increased sensitivity to dioxin-induced gene expression, toxicity, steatohepatitis and lethality. Tiparp-/- mice given a single injection of 100 µg/kg or 10 µg/kg dioxin do not survive beyond day 5 and 8, respectively; all Tiparp+/+ mice survived the 30 day treatment. TIPARP ADP-ribosylates AHR, but not its dimerization partner the AHR nuclear translocator (ARNT), and the repressive effects of TIPARP on AHR are reversed by the macrodomain containing mono-ADP-ribosylase MacroD1, but not MacroD2. These data reveal previously unidentified roles for TIPARP, MacroD1, and ADP-ribosylation in AHR-mediated steatohepatitis and lethality in response to dioxin.

 

Chairperson: Marit Bakke <marit.bakke@uib.no>, Department of Biomedicine