Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol

2002 ◽  
Vol 62 (5) ◽  
pp. 975-982 ◽  
Author(s):  
Eunseon Hur ◽  
Hong-Hee Kim ◽  
Su Mi Choi ◽  
Jin Hee Kim ◽  
Sujin Yim ◽  
...  
Keyword(s):  
Heat Shock ◽  
Dna Binding ◽  
Heat Shock Protein ◽  
Aryl Hydrocarbon Receptor ◽  
Hypoxia Inducible Factor ◽  
Protein Inhibitor ◽  
Hypoxia Inducible Factor 1Α ◽  
Aryl Hydrocarbon

scholarly journals Transformation of the aryl hydrocarbon receptor to a DNA-binding form is accompanied by release of the 90 kDa heat-shock protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin

1993 ◽  
Vol 294 (1) ◽  
pp. 95-101 ◽  
Author(s):  
E C Henry ◽  
T A Gasiewicz
Keyword(s):  
Heat Shock ◽  
Dna Binding ◽  
Heat Shock Protein ◽  
Aryl Hydrocarbon Receptor ◽  
Incubation Temperature ◽  
Binding Affinities ◽  
Aryl Hydrocarbon ◽  
Molecular Events ◽  
Binding Forms ◽  
Tetrachlorodibenzo P Dioxin

The binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the aryl hydrocarbon receptor (AhR) elicits a sequence of poorly defined molecular events that ultimately yield a heteromeric transformed AhR that is active as a transcription factor. We have previously developed a model of the ligand-initiated transformation of the AhR to the DNA-binding state based on characterization of several forms of the AhR with respect to their physicochemical properties and DNA-binding affinities. The present studies were designed to determine whether, and at what stage, this process of transformation alters the receptor's affinity for TCDD. In rat hepatic cytosol, approx. 10% of the TCDD specifically bound to the AhR rapidly dissociated (t1/2 approximately 1 h), while the remainder was only slowly dissociable (t1/2 approximately 70 h). The isolated DNA-binding forms of the receptor (monomeric and transformed) bound TCDD very tightly (t1/2 > 100 h), whereas TCDD was dissociable from the non-DNA-binding receptor form(s). A lower incubation temperature (0-4 degrees C) and the presence of molybdate partially stabilized the non-DNA-binding fraction of the TCDD.receptor complex and also enhanced TCDD dissociation in crude cytosol. Immunoprecipitation of the different AhR forms with an anti-AhR antibody and immunoblotting with antibody to the 90 kDa heat-shock protein (hsp90) demonstrated that hsp90 was associated with the unoccupied receptor complex as well as with a fraction of the non-DNA-binding TCDD.receptor complex; isolated DNA-binding forms did not contain detectable hsp90. We conclude that while hsp90 remains associated with the AhR, TCDD is readily dissociable; following release of hsp90, however, TCDD becomes very tightly bound, and remains so upon completion of transformation.

scholarly journals p23 protects the human aryl hydrocarbon receptor from degradation via a heat shock protein 90-independent mechanism

2018 ◽  
Vol 152 ◽  
pp. 34-44 ◽  
Author(s):  
Beverly Pappas ◽  
Yujie Yang ◽  
Yu Wang ◽  
Kyung Kim ◽  
Hee Jae Chung ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Aryl Hydrocarbon Receptor ◽  
Heat Shock Protein 90 ◽  
Aryl Hydrocarbon ◽  
Independent Mechanism

scholarly journals Heat Induction of the Unphosphorylated Form of Hypoxia-inducible Factor-1α Is Dependent on Heat Shock Protein-90 Activity

2002 ◽  
Vol 277 (11) ◽  
pp. 9262-9267 ◽  
Author(s):  
Dörthe M. Katschinski ◽  
Lu Le ◽  
Daniel Heinrich ◽  
Klaus F. Wagner ◽  
Thomas Hofer ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Hypoxia Inducible Factor ◽  
Heat Shock Protein 90 ◽  
Heat Induction ◽  
Hypoxia Inducible Factor 1Α

scholarly journals Hypoxia-Inducible Factor 1α (HIF1α) Suppresses Virus Replication in Human Cytomegalovirus Infection by Limiting Kynurenine Synthesis

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lisa M. Wise ◽  
Yuecheng Xi ◽  
John G. Purdy
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Virus Replication ◽  
Human Cytomegalovirus ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α ◽  
Indoleamine 2,3 Dioxygenase ◽  
Aryl Hydrocarbon ◽  
Infected Cells ◽  
Hcmv Replication ◽  
Rate Limiting

ABSTRACT Human cytomegalovirus (HCMV) replication depends on the activities of several host regulators of metabolism. Hypoxia-inducible factor 1α (HIF1α) was previously proposed to support virus replication through its metabolic regulatory function. HIF1α protein levels rise in response to HCMV infection in nonhypoxic conditions, but its effect on HCMV replication was not investigated. We addressed the role of HIF1α in HCMV replication by generating primary human cells with HIF1α knocked out using CRISPR/Cas9. When HIF1α was absent, we found that HCMV replication was enhanced, showing that HIF1α suppresses viral replication. We used untargeted metabolomics to determine if HIF1α regulates metabolite concentrations in HCMV-infected cells. We discovered that in HCMV-infected cells, HIF1α suppresses intracellular and extracellular concentrations of kynurenine. HIF1α also suppressed the expression of indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme in kynurenine synthesis. In addition to its role in tryptophan metabolism, kynurenine acts as a signaling messenger by activating aryl hydrocarbon receptor (AhR). Inhibiting AhR reduces HCMV replication, while activating AhR with an exogenous ligand increases virus replication. Moreover, we found that feeding kynurenine to cells promotes HCMV replication. Overall, our findings indicate that HIF1α reduces HCMV replication by regulating metabolism and metabolite signaling. IMPORTANCE Viruses, including human cytomegalovirus (HCMV), reprogram cellular metabolism using host metabolic regulators to support virus replication. Alternatively, in response to infection, the host can use metabolism to limit virus replication. Here, our findings show that the host uses hypoxia-inducible factor 1α (HIF1α) as a metabolic regulator to reduce HCMV replication. Further, we found that HIF1α suppresses kynurenine synthesis, a metabolite that can promote HCMV replication by signaling through the aryl hydrocarbon receptor (AhR). In infected cells, the rate-limiting enzyme in kynurenine synthesis, indoleamine 2,3-dioxygenase 1 (IDO1), is suppressed by a HIF1α-dependent mechanism. Our findings describe a functional connection between HIF1α, IDO1, and AhR that allows HIF1α to limit HCMV replication through metabolic regulation, advancing our understanding of virus-host interactions.

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