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Open AccessArticle

Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

1
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan
2
Healthy Aging Research Center, Chang Gung University, Tao-yuan 333, Taiwan
3
Department of Laboratory Medicine, Chang Gung Memorial Hospital, Lin-Kou 333, Taiwan
4
Molecular Medicine Research Center, Chang Gung University, Tao-yuan 333, Taiwan
5
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Curt Hagedorn
Viruses 2015, 7(12), 6689-6706; https://doi.org/10.3390/v7122966
Received: 7 October 2015 / Revised: 7 December 2015 / Accepted: 10 December 2015 / Published: 17 December 2015
(This article belongs to the Section Antivirals & Vaccines)
Glucose-6-phosphate dehydrogenase (G6PD)-deficient cells are highly susceptible to viral infection. This study examined the mechanism underlying this phenomenon by measuring the expression of antiviral genes—tumor necrosis factor alpha (TNF-α) and GTPase myxovirus resistance 1 (MX1)—in G6PD-knockdown cells upon human coronavirus 229E (HCoV-229E) and enterovirus 71 (EV71) infection. Molecular analysis revealed that the promoter activities of TNF-α and MX1 were downregulated in G6PD-knockdown cells, and that the IκB degradation and DNA binding activity of NF-κB were decreased. The HSCARG protein, a nicotinamide adenine dinucleotide phosphate (NADPH) sensor and negative regulator of NF-κB, was upregulated in G6PD-knockdown cells with decreased NADPH/NADP+ ratio. Treatment of G6PD-knockdown cells with siRNA against HSCARG enhanced the DNA binding activity of NF-κB and the expression of TNF-α and MX1, but suppressed the expression of viral genes; however, the overexpression of HSCARG inhibited the antiviral response. Exogenous G6PD or IDH1 expression inhibited the expression of HSCARG, resulting in increased expression of TNF-α and MX1 and reduced viral gene expression upon virus infection. Our findings suggest that the increased susceptibility of the G6PD-knockdown cells to viral infection was due to impaired NF-κB signaling and antiviral response mediated by HSCARG. View Full-Text
Keywords: G6PD; NADPH; coronavirus; enterovirus; antiviral response; HSCARG G6PD; NADPH; coronavirus; enterovirus; antiviral response; HSCARG
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MDPI and ACS Style

Wu, Y.-H.; Chiu, D.T.-Y.; Lin, H.-R.; Tang, H.-Y.; Cheng, M.-L.; Ho, H.-Y. Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling. Viruses 2015, 7, 6689-6706.

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