scholarly journals Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity

2021 ◽  
Vol 22 (11) ◽  
pp. 6097
Author(s):  
Yujie Yang ◽  
William K. Chan

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which is involved in diverse cellular events in humans. The most well-characterized function of AHR is its ability to upregulate gene transcription after exposure to its ligands, such as environmental toxicants, dietary antioxidants, drugs, and endogenous ligands. The cellular content of AHR is partly controlled by its degradation via the ubiquitin–proteasome system and the lysosome-dependent autophagy. We used human cervical cancer (HeLa) cells to investigate how AHR undergoes protein degradation and how its activity is modulated. Since the glycogen synthase kinase 3 beta (GSK3β)-mediated phosphorylation can trigger protein degradation and substrates of GSK3β contain stretches of serine/threonine residues which can be found in AHR, we examined whether degradation and activity of AHR can be controlled by GSK3β. We observed that AHR undergoes the GSK3β-dependent, LC3-mediated lysosomal degradation without ligand treatment. The AHR can be phosphorylated in a GSK3β-dependent manner at three putative sites (S436/S440/S444, S689/S693/T697, and S723/S727/T731), which leads to lysosomal degradation of the AHR protein. Inhibition of the GSK3β activity suppresses the ligand-activated transcription of an AHR target gene in HeLa, human liver cancer (Hep3B), and human breast cancer (MCF-7) cells. Collectively, our findings support that phosphorylation of AHR by GSK3β is essential for the optimal activation of its target gene transcription and this phosphorylation may partake as an “off” switch by subjecting the receptor to lysosomal degradation.

2013 ◽  
Vol 34 (7) ◽  
pp. 1759-1771 ◽  
Author(s):  
Diana A.T. Nijholt ◽  
Anna Nölle ◽  
Elise S. van Haastert ◽  
Hessel Edelijn ◽  
Ruud F. Toonen ◽  
...  

2004 ◽  
Vol 101 (24) ◽  
pp. 9085-9090 ◽  
Author(s):  
Markus Welcker ◽  
Amir Orian ◽  
Jianping Jin ◽  
Jonathan A. Grim ◽  
J. Wade Harper ◽  
...  

2000 ◽  
Vol 20 (18) ◽  
pp. 6712-6720 ◽  
Author(s):  
Tomoko Andoh ◽  
Yuzoh Hirata ◽  
Akira Kikuchi

ABSTRACT The yeast Saccharomyces cerevisiae has four genes,MCK1, MDS1 (RIM11),MRK1, and YOL128c, that encode glycogen synthase kinase 3 (GSK-3) homologs. The gsk-3 null mutant, in which these four genes are disrupted, shows temperature sensitivity, which is suppressed by the expression of mammalian GSK-3β and by an osmotic stabilizer. Suppression of temperature sensitivity by an osmotic stabilizer is also observed in the bul1 bul2 double null mutant, and the temperature sensitivity of the bul1 bul2 double null mutant is suppressed by multiple copies ofMCK1. We have screened rog mutants (revertants of gsk-3) which suppress the temperature sensitivity of themck1 mds1 double null mutant and found that two of them,rog1 and rog2, also suppress the temperature sensitivity of the bul1 bul2 double null mutant. Bul1 and Bul2 have been reported to bind to Rsp5, a hect (for homologous to E6-associated-protein carboxyl terminus)-type ubiquitin ligase, but involvement of Bul1 and Bul2 in protein degradation has not been demonstrated. We find that Rog1, but not Rog2, is stabilized in thegsk-3 null and the bul1 bul2 double null mutants. Rog1 binds directly to Rsp5, and their interaction is dependent on GSK-3. Furthermore, Rog1 is stabilized in thenpi1 mutant, in which RSP5 expression levels are reduced. These results suggest that yeast GSK-3 regulates the stability of Rog1 in cooperation with Bul1, Bul2, and Rsp5.


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