Hypoxia Inducible Factor-1α-Independent Suppression of Aryl Hydrocarbon Receptor-Regulated Genes by Nickel

2003 ◽  
Vol 64 (6) ◽  
pp. 1485-1493 ◽  
Author(s):  
Todd Davidson ◽  
Konstantin Salnikow ◽  
Max Costa
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α ◽  
Aryl Hydrocarbon

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.

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

2021 ◽  
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

AbstractHuman 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 non-hypoxic 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 the indoleamine 2,3-dioxygenase 1 (IDO1) 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 HCMV 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.ImportanceViruses, like 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.

Significance of Prolyl Hydroxylase 2 in the Interference of Aryl Hydrocarbon Receptor and Hypoxia-Inducible Factor-1α Signaling

2008 ◽  
Vol 21 (2) ◽  
pp. 341-348 ◽  
Author(s):  
Anja Seifert ◽  
Dörthe M. Katschinski ◽  
Sarah Tonack ◽  
Bernd Fischer ◽  
Anne Navarrete Santos
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1Α ◽  
Aryl Hydrocarbon

Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX

2009 ◽  
Vol 419 (2) ◽  
pp. 419-425 ◽  
Author(s):  
Martina Takacova ◽  
Tereza Holotnakova ◽  
Jan Vondracek ◽  
Miroslav Machala ◽  
Katerina Pencikova ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Aryl Hydrocarbon Receptor ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Carbonic Anhydrase Ix ◽  
Independent Manner ◽  
Hypoxic Induction ◽  
Aryl Hydrocarbon ◽  
Ca Ix ◽  
Tcdd Treatment

Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1α and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1α competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.

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