Roles of the ubiquitin ligase CUL4B and ADP-ribosyltransferase TiPARP in TCDD-induced nuclear export and proteasomal degradation of the transcription factor AHR
| Autor: | Pengbo Zhou, Chenyi Yang, Arleen B. Rifkind, Silvia Diani-Moore, Mercedes Paz Rijo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Polychlorinated Dibenzodioxins NES nuclear export signal TCDD 2 3 7 8-tetrachlorodibenzo-p-dioxin Biochemistry cytochrome P450 (CYP450) Mice +siTiPARP silencing TiPARP by siRNA AHR aryl hydrocarbon receptor 2 3 7 8-tetrachlorodibenzo-p-dioxin (TCDD dioxin) Basic Helix-Loop-Helix Transcription Factors mouse embryonic fibroblasts (MEFs) Cells Cultured biology Chemistry respiratory system Cullin Proteins Ubiquitin ligase Cell biology E3 ubiquitin ligase Gene Knockdown Techniques Infb1 interferon beta 1 Environmental Pollutants nuclear export Poly(ADP-ribose) Polymerases Research Article Proteasome Endopeptidase Complex Aryl hydrocarbon receptor nuclear translocator 3pRNA 5'-triphosphate RNA sgRNA single-guide RNA CUL4B cullin 4B Protein degradation 03 medical and health sciences FBS fetal bovine serum TCDD-Inducible Poly [ADP-Ribose] Polymerase Animals MEFCul4b-null MEF cell line in which the Cullin 4B gene had been knocked out Nuclear export signal Molecular Biology Transcription factor aryl hydrocarbon receptor (AHR) 030102 biochemistry & molecular biology Cell Biology RT-qPCR real-time quantitative PCR Aryl hydrocarbon receptor MEF mouse embryonic fibroblast respiratory tract diseases TCDD-inducible poly(ADP-ribose) polymerase (TiPARP PARP7 ARTD14) TiPARP TCDD-inducible poly(ADP-ribose) polymerase 030104 developmental biology Proteasome Gene Expression Regulation Receptors Aryl Hydrocarbon protein proteasomal degradation Proteolysis ARNT aryl hydrocarbon receptor nuclear translocator biology.protein interferon beta 1 (Ifnb1) cullin 4B (CUL4B) LMB leptomycin B |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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