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

Viruses. 2015 Dec 17;7(12):6689-706. doi: 10.3390/v7122966.


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.

Keywords: G6PD; HSCARG; NADPH; antiviral response; coronavirus; enterovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Coronavirus 229E, Human / immunology*
  • Enterovirus A, Human / immunology*
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Fibroblasts / immunology
  • Fibroblasts / 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


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