Abstract
The aryl hydrocarbon receptor (AHR) is a transcription factor activated by exogenous halogenated polycyclic aromatic hydrocarbon compounds, including the environmental toxin TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and naturally occurring dietary and endogenous compounds. The activated AHR enhances transcription of specific genes including phase I and phase II metabolism enzymes and other targets genes such as the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). The regulation of AHR activation is a dynamic process: immediately after transcriptional activation of the AHR by TCDD, the AHR is exported from the nucleus to the cytoplasm where it is subjected to proteasomal degradation. However, the mechanisms regulating AHR degradation are not well understood. Here, we studied the role of two enzymes reported to enhance AHR breakdown: the cullin 4B (CUL4B)AHR complex, an E3 ubiquitin ligase that targets the AHR and other proteins for ubiquitination, and TiPARP, which targets proteins for ADP-ribosylation, a posttranslational modification that can increase susceptibility to degradation. Using a WT mouse embryonic fibroblast (MEF) cell line and an MEF cell line in which CUL4B has been deleted (MEFCul4b-null), we discovered that loss of CUL4B partially prevented AHR degradation after TCDD exposure, while knocking down TiPARP in MEFCul4b-null cells completely abolished AHR degradation upon TCDD treatment. Increased TCDD-activated AHR protein levels in MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down led to enhanced AHR transcriptional activity, indicating that CUL4B and TiPARP restrain AHR action. This study reveals a novel function of TiPARP in controlling TCDD-activated AHR nuclear export and subsequent proteasomal degradation.
Highlights
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), a byproduct of incineration and other industrial processes, is a ubiquitous environmental contaminant whose toxic effects, In memory of Dr Arleen B
Using genetically engineered mouse embryonic fibroblast (MEF) cell lines, we studied the roles of two factors that affect aryl hydrocarbon receptor (AHR) protein stability: the E3 ubiquitin ligase CUL4BAHR complex and the AHR target gene, TCDD-inducible poly(ADP-ribose) polymerase (TiPARP)
We report here the discoveries that are as follows: [1] cullin 4B (CUL4B) and TiPARP collaborate to promote AHR protein degradation; [2] TiPARP has a greater effect than CUL4B in promoting AHR proteasomal degradation; and [3] loss of both CUL4B and TiPARP completely prevent TCDD-induced AHR degradation
Summary
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), a byproduct of incineration and other industrial processes, is a ubiquitous environmental contaminant whose toxic effects, In memory of Dr Arleen B.
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