title: 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.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan. yihsuanwu@mail.cgu.edu.tw.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan. dtychiu@mail.cgu.edu.tw.|Healthy Aging Research Center, Chang Gung University, Tao-yuan 333, Taiwan. dtychiu@mail.cgu.edu.tw.|Department of Laboratory Medicine, Chang Gung Memorial Hospital, Lin-Kou 333, Taiwan. dtychiu@mail.cgu.edu.tw.
authors.forename: Daniel Tsun-Yee
authors.initials: DT
authors.lastname: Chiu
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Tao-yuan 333, Taiwan. rebecca19852006@hotmail.com.
authors.forename: Hsin-Ru
authors.initials: HR
authors.lastname: Lin
authors.affiliation: Healthy Aging Research Center, Chang Gung University, Tao-yuan 333, Taiwan. tangshyu@gmail.com.
authors.forename: Hsiang-Yu
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan. chengm@mail.cgu.edu.tw.|Healthy Aging Research Center, Chang Gung University, Tao-yuan 333, Taiwan. chengm@mail.cgu.edu.tw.|Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan. chengm@mail.cgu.edu.tw.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-yuan 333, Taiwan. hoh01@mail.cgu.edu.tw.|Healthy Aging Research Center, Chang Gung University, Tao-yuan 333, Taiwan. hoh01@mail.cgu.edu.tw.
authors.forename: Hung-Yao
authors.initials: HY
authors.lastname: Ho
mesh_terms: D002460:Cell Line; D028941:Coronavirus 229E, Human / Q000276:immunology*; D029821:Enterovirus A, Human / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006801:Humans; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016328:NF-kappa B; C520476:NMRAL1 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D005954:Glucosephosphate Dehydrogenase
keywords: G6PD; HSCARG; NADPH; antiviral response; coronavirus; enterovirus