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

Abstract

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.

• Authors: Yi-Hsuan Wu, Daniel Tsun-Yee Chiu, Hsin-Ru Lin, Hsiang-Yu Tang, Mei-Ling Cheng, Hung-Yao Ho
• Journal: Viruses (Viruses) Vol. 7 Issue 12 Pg. 6689-706 (Dec 17 2015) ISSN: 1999-4915 [Electronic] Switzerland
• PMID: 26694452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MX1 protein, human
• Myxovirus Resistance Proteins
• NF-kappa B
• NMRAL1 protein, human
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Glucosephosphate Dehydrogenase

Topics

• Cell Line
• Coronavirus 229E, Human (immunology)
• Enterovirus A, Human (immunology)
• Epithelial Cells (immunology, virology)
• Fibroblasts (immunology, virology)
• Gene Expression Regulation
• Gene Knockdown Techniques
• Glucosephosphate Dehydrogenase (metabolism)
• Humans
• Myxovirus Resistance Proteins (metabolism)
• NF-kappa B (metabolism)
• Signal Transduction
• Transcription Factors (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (metabolism)