Glucose-6-Phosphate Dehydrogenase Deficiency Enhances Human Coronavirus 229E Infection

Wu, Yi‐Hsuan; Tseng, Ching Ping; Cheng, Mei‐Ling; Ho, Hung‐Yao; Shih, Shin‐Ru; Chiu, Daniel T.

doi:10.1086/528377

Cited by 115 publications

(153 citation statements)

References 15 publications

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“…According to our findings, this form binds to ssRNA more tightly than does the reduced form, and could therefore promote replication of the viral genome. This speculation is supported by the recent report by Wu et al 58 who have shown that oxidative stress in the host cell promotes HCoV-229E infectivity. Very likely, SARS-CoV will also induce oxidative stress in the infected host cell, 59 even though its Nsp9 does not seem to form disulfide-linked dimers, at least not in vitro.…”

Section: Discussionmentioning

confidence: 56%

Variable Oligomerization Modes in Coronavirus Non-structural Protein 9

Ponnusamy

Moll

Weimar

et al. 2008

Journal of Molecular Biology

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Non-structural protein 9 (Nsp9) of coronaviruses is believed to bind single-stranded RNA in the viral replication complex. The crystal structure of Nsp9 of human coronavirus (HCoV) 229E reveals a novel disulfide-linked homodimer, which is very different from the previously reported Nsp9 dimer of SARS coronavirus. In contrast, the structure of the Cys69Ala mutant of HCoV-229E Nsp9 shows the same dimer organization as the SARS-CoV protein. In the crystal, the wild-type HCoV-229E protein forms a trimer of dimers, whereas the mutant and SARS-CoV Nsp9 are organized in rod-like polymers. Chemical cross-linking suggests similar modes of aggregation in solution. In zone-interference gel electrophoresis assays and surface plasmon resonance experiments, the HCoV-229E wild-type protein is found to bind oligonucleotides with relatively high affinity, whereas binding by the Cys69Ala and Cys69Ser mutants is observed only for the longest oligonucleotides. The corresponding mutations in SARS-CoV Nsp9 do not hamper nucleic acid binding. From the crystal structures, a model for single-stranded RNA binding by Nsp9 is deduced. We propose that both forms of the Nsp9 dimer are biologically relevant; the occurrence of the disulfide-bonded form may be correlated with oxidative stress induced in the host cell by the viral infection.

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Section: Discussionmentioning

confidence: 56%

Variable Oligomerization Modes in Coronavirus Non-structural Protein 9

Ponnusamy

Moll

Weimar

et al. 2008

Journal of Molecular Biology

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“…The milieu inside or at the surface of these vesicles is unknown, but it is well possible that it is partially oxidative. It has also been speculated [25] that formation of disulfide bonds may be a way for the coronaviral Nsps to function in the presence of the oxidative stress that is the consequence of the viral infection [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

Tan¹,

Hilgenfeld²

2009

SciVee

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Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the three-dimensional structures of several of the replicase/transcriptase components of SARS coronavirus (SARS-CoV), the non-structural proteins (Nsps), have been determined. However, within the large Nsp3 (1922 amino-acid residues), the structure and function of the so-called SARSunique domain (SUD) have remained elusive. SUD occurs only in SARS-CoV and the highly related viruses found in certain bats, but is absent from all other coronaviruses. Therefore, it has been speculated that it may be involved in the extreme pathogenicity of SARS-CoV, compared to other coronaviruses, most of which cause only mild infections in humans. In order to help elucidate the function of the SUD, we have determined crystal structures of fragment 389-652 (''SUD core '') of Nsp3, which comprises 264 of the 338 residues of the domain. Both the monoclinic and triclinic crystal forms (2.2 and 2.8 Å resolution, respectively) revealed that SUD core forms a homodimer. Each monomer consists of two subdomains, SUD-N and SUD-M, with a macrodomain fold similar to the SARS-CoV X-domain. However, in contrast to the latter, SUD fails to bind ADP-ribose, as determined by zone-interference gel electrophoresis. Instead, the entire SUD core as well as its individual subdomains interact with oligonucleotides known to form G-quadruplexes. This includes oligodeoxy-as well as oligoribonucleotides. Mutations of selected lysine residues on the surface of the SUD-N subdomain lead to reduction of Gquadruplex binding, whereas mutations in the SUD-M subdomain abolish it. As there is no evidence for Nsp3 entering the nucleus of the host cell, the SARS-CoV genomic RNA or host-cell mRNA containing long G-stretches may be targets of SUD. The SARS-CoV genome is devoid of G-stretches longer than 5-6 nucleotides, but more extended G-stretches are found in the 39-nontranslated regions of mRNAs coding for certain host-cell proteins involved in apoptosis or signal transduction, and have been shown to bind to SUD in vitro. Therefore, SUD may be involved in controlling the host cell's response to the viral infection. Possible interference with poly(ADP-ribose) polymerase-like domains is also discussed.

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“…5, 6, 7, 8, 9 However, during the past decade, accumulating evidence has demonstrated that G6PD deficiency also affects nucleated cells 10, 11, 12, 13, 14 and cellular pathophysiological events, including dysregulated cell proliferation, accelerated cellular senescence, enhanced susceptibility to viral infection, and impaired embryonic development. 15, 16 G6PD is essential for normal cell growth and survival. For example, G6PD-deficient fibroblasts exhibit retarded growth and premature senescence.…”

mentioning

confidence: 99%

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

Yang

et al. 2013

Cell Death Dis

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Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.

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Glucose-6-Phosphate Dehydrogenase Deficiency Enhances Human Coronavirus 229E Infection

Cited by 115 publications

References 15 publications

Variable Oligomerization Modes in Coronavirus Non-structural Protein 9

Variable Oligomerization Modes in Coronavirus Non-structural Protein 9

The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

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