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.

Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

“…Using plaque assay, we found that the progeny viral particle derived from infected G6PD- G6PD Status Affects TNF-α-Triggered COX-2 Response kd cells was significantly higher compared with infected scramble control cells and the amount of viral particles was comparable with viral N gene expression ( Fig 1E). These findings are consistent with our previous findings [26,32]. We further analyzed whether impaired COX-2/ PGE 2 expression via TNF-α stimulation plays a role in increasing viral replication in G6PD-kd cells and used viral gene expression to represent viral replication.…”

G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg?

“…There is now accumulating evidence that G6PD de ciency affects cells other than erythrocytes 10,[21][22][23][24] . The replication and spread of respiratory viruses normally involves activation of the antiviral innate immune responses and culminates in the production of type I interferons (IFNs) and proin ammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which in turn upregulate antiviral proteins 24 .…”

The association between low glucose-6-phosphate dehydrogenase activity level and hepatitis B virus infection among pre-pregnant reproductive-age Chinese females

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Most researchers explained the potential mechanism by which LG6PD could result in the disorder of oxidative stress and hence, in the malfunctioning of granulocytes [30][31][32][33] . Some researchers 5,30 suggested that LG6PD could reduce NADPH levels, thus decrease the production of nitric oxide, superoxide and hydrogen peroxide in leucocytes, and weaken the immune function thereof, thereby increase the susceptibility to pathogens.…”

“…Wu et al 6 suggested that G6PD-knockdown cells could produce more reactive oxygen species, and high oxidative stress condition favors viral replication since it promotes viral gene expression. Other mechanism studies showed that LG6PD could affect the redox condition thereby affect the HSCARG-NF-κB (a newly identified nuclear factor κB) signaling axis, which could stimulate the expression of antiviral genes and induce susceptibility of the body cells to viruses 33 . Therefore, there are sufficient mechanisms reported in research findings to support the notion that LG6PD could enhance the susceptibility to virus infections.…”

“…and serological test results. Age was split into three groups (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), and 40-49 years old), while nationality was categorized as 'Han' and 'others' . Educational level was categorized into two groups (bachelor degree or above, high school or below).…”