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Post-Translational Modification and Degradation Mechanisms of the Aryl Hydrocarbon Receptor.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Post-Translational Modification and Degradation Mechanisms of the Aryl Hydrocarbon Receptor./
Author:	Yang, Yujie.
Description:	1 online resource (170 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28643736click for full text (PQDT)
ISBN:	9798534681703

Post-Translational Modification and Degradation Mechanisms of the Aryl Hydrocarbon Receptor.
Yang, Yujie.

Post-Translational Modification and Degradation Mechanisms of the Aryl Hydrocarbon Receptor. - 1 online resource (170 pages)

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--University of the Pacific, 2021.

Includes bibliographical references

The aryl hydrocarbon receptor (AHR) is a transcription factor first discovered to be activated by exogenous ligands, such as dioxins, and helps promote downstream gene (e.g. CYP1A1) transcription to metabolize the toxicants. With the reports of various AHR targets genes, the expression levels and activities of AHR have been implicated in many physiological and pathological situations. Understanding how AHR protein level is regulated would provide more information to target AHR. AHR stays in the cytosol in the absence of ligand in a complex with HSP90, p23 and XAP2. After ligand activation, AHR translocates into the nucleus, fulfilling its transactivation function and then is finally degraded by proteasomes. Here, we discovered a new mechanism that controls basal AHR protein level: the selective autophagy. Loss of AHR co-chaperone p23 leads to increased protein degradation of AHR through autophagy in HeLa cells. Inhibition of autophagy using several inhibitors (chloroquine, bafilomycin A1 or 3-methyladenine) increased AHR protein levels. Knocking down of key macroautophagy protein LC3B increases AHR protein levels and decreases the responsiveness of AHR to CQ treatment. The interaction between AHR and LC3B as well as AHR and autophagy receptor p62 were confirmed in vitro and in situ. AHR is found to be lysine (K) 63-ubiquitinated in HeLa cells, which is a common signal for the autophagy-lysosomal degradation.We also discovered that AHR is controlled by glycogen synthase kinase 3β(GSK3β) phosphorylation. Inhibition of GSK3β activity or its expression level increased AHR protein levels while expression of HA tagged-GSK3β lowers AHR protein levels. AHR protein level is regulated through autophagy. We confirmed the GSK3β-mediated phosphorylation of AHR by phos-tag gel electrophoresis couples with Western blot analysis and identified three putative phosphorylation sites of AHR in the C-terminal half of AHR sequence. Moreover, phosphorylated AHR constitutes the active pool for transactivation and phosphorylation tagged AHR for the autophagy-lysosomal degradation, which may act as way to limit its function.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798534681703Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Aryl hydrocarbon receptorIndex Terms--Genre/Form:

542853
Electronic books.

Post-Translational Modification and Degradation Mechanisms of the Aryl Hydrocarbon Receptor.
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