Inhibitory effects of glutathione on dengue virus production

Tian, Yanping; Jiang, Wanling; Gao, Na; Zhang, Junlei; Chen, Wei; Fan, Dongying; Zhou, Dujin; An, Jing

doi:10.1016/j.bbrc.2010.05.108

Cited by 43 publications

(38 citation statements)

References 19 publications

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“…However, strong upregulation of this enzyme was detected in DENV-infected mosquito cells [64]. In other studies, decreased intracellular GSH levels were found in DENV-infected HepG2 cells [65] as well as in other types of cells infected with Sendai virus, influenza virus, or hepatitis C virus [57, 66, 67]. In contrast, in the present study, both a ThioTracker fluorescent assay and a colorimetric assay detected elevated GSH levels in WNV-infected BHK cells by 8 hpi and additional data indicated that multiple antioxidant pathway components were also upregulated by WNV-infection.…”

Section: Discussionmentioning

confidence: 99%

Arsenite-induced stress granule formation is inhibited by elevated levels of reduced glutathione in West Nile virus-infected cells

2017

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Oxidative stress activates the cellular kinase HRI, which then phosphorylates eIF2α, resulting in stalled translation initiation and the formation of stress granules (SGs). SG assembly redirects cellular translation to stress response mRNAs and inhibits cap-dependent viral RNA translation. Flavivirus infections were previously reported to induce oxidative stress in infected cells but flavivirus-infected cells paradoxically develop resistance to arsenite (Ars)-induced SG formation with time after infection. This resistance was previously postulated to be due to sequestration of the SG protein Caprin1 by Japanese encephalitis virus capsid protein. However, Caprin1 did not co-localize with West Nile virus (WNV) capsid protein in infected cells. Other stressors induced SGs with equal efficiency in mock- and WNV-infected cells indicating the intrinsic ability of cells to assemble SGs was not disabled. Induction of both reactive oxygen species (ROS) and the antioxidant response was detected at early times after WNV-infection. The transcription factors, Nrf2 and ATF4, which activate antioxidant genes, were upregulated and translocated to the nucleus. Knockdown of Nrf2, ATF4 or apoptosis-inducing factor (AIF), a mitochondrial protein involved in regenerating intracellular reduced glutathione (GSH) levels, with siRNA or treatment of cells with buthionine sulphoximine, which induces oxidative stress by inhibiting GSH synthesis, decreased intracellular GSH levels and increased the number of SG-positive, infected cells. Mitochondria were protected from Ars-induced damage by WNV infection until late times in the infection cycle. The results indicate that the increase in virus-induced ROS levels is counterbalanced by a virus-induced antioxidant response that is sufficient to also overcome the increase in ROS induced by Ars treatment and prevent Ars-induced SG assembly and mitochondrial damage. The virus-induced alterations in the cellular redox status appear to provide benefits for the virus during its lifecycle.

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Section: Discussionmentioning

confidence: 99%

Arsenite-induced stress granule formation is inhibited by elevated levels of reduced glutathione in West Nile virus-infected cells

2017

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“…It is becoming increasingly clear that oxidative stress and cellular responses to it play critical roles in modulating a large number of biological processes, including pathogenesis by bacterial and viral infections. Many viruses, including HSV, have been shown to induce oxidative stress, and antioxidants have shown promise in the treatment of viral infection (54)(55)(56)(59)(60)(61)(62)(63). Viral proteins that play roles in sensing and responding to changes in redox status may thus provide targets for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

Albright

Kosinski

Szczepaniak

et al. 2015

J Virol

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During DNA encapsidation, herpes simplex virus 1 (HSV-1) procapsids are converted to DNA-containing capsids by a process involving activation of the viral protease, expulsion of the scaffold proteins, and the uptake of viral DNA. Encapsidation requires six minor capsid proteins (UL6, UL15, UL17, UL25, UL28, and UL33) and one viral protein, UL32, not found to be associated with capsids. Although functions have been assigned to each of the minor capsid proteins, the role of UL32 in encapsidation has remained a mystery. Using an HSV-1 variant containing a functional hemagglutinin-tagged UL32, we demonstrated that UL32 was synthesized with true late kinetics and that it exhibited a previously unrecognized localization pattern. At 6 to 9 h postinfection (hpi), UL32 accumulated in viral replication compartments in the nucleus of the host cell, while at 24 hpi, it was additionally found in the cytoplasm. A newly generated UL32-null mutant was used to confirm that although B capsids containing wild-type levels of capsid proteins were synthesized, these procapsids were unable to initiate the encapsidation process. Furthermore, we showed that UL32 is redox sensitive and identified two highly conserved oxidoreductase-like C-X-X-C motifs that are essential for protein function. In addition, the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, were altered in the absence of UL32, suggesting that UL32 may act to modulate disulfide bond formation during procapsid assembly and maturation. IMPORTANCEAlthough functions have been assigned to six of the seven required packaging proteins of HSV, the role of UL32 in encapsidation has remained a mystery. UL32 is a cysteine-rich viral protein that contains C-X-X-C motifs reminiscent of those in proteins that participate in the regulation of disulfide bond formation. We have previously demonstrated that disulfide bonds are required for the formation and stability of the viral capsids and are also important for the formation and stability of the UL6 portal ring. In this report, we demonstrate that the disulfide bond profiles of the viral proteins UL6, UL25, and VP19C and the viral protease, VP24, are altered in cells infected with a newly isolated UL32-null mutant virus, suggesting that UL32 acts as a chaperone capable of modulating disulfide bond formation. Furthermore, these results suggest that proper regulation of disulfide bonds is essential for initiating encapsidation.T he products of herpes simplex virus 1 (HSV-1) DNA replication are head-to-tail concatemers that are resolved into monomeric genomic units and packaged into a procapsid shell in the nucleus of the infected cell (reviewed in references 1 to 3). The procapsid is comprised of the major capsid protein (VP5), triplex proteins (VP19C and VP23), and a dodecameric UL6 portal ring. The precursor of the viral protease (UL26) and the scaffolding protein (UL26.5) form a scaffold around which the capsid shell assembles (3, 4). During DNA encapsidation, the viral protease (V...

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“…In fact, Tian et al (2010) have demonstrated that DV serotype 2 (DV2) infection resulted in a decrease in intracellular GSH level, which caused NF-κB activation and increased DV2 production (Tian et al, 2010). Supplemental GSH significantly inhibited activation of NF-κB, resulting in a decreased production of DV2 in HepG2 cells.…”

Section: Gsh and Viral Infectionmentioning

confidence: 99%

“…In conclusion, DV2 infection could reduce host intracellular GSH concentration and benefited from this process. Supplemental GSH could inhibit viral production, indicating that GSH might be valuable in the prevention and treatment of DV2 infection (Tian et al, 2010). Additionally, it has been demonstrated that also chronic hepatitis C virus (HCV) infection in hepatocyte cell lines led to a decreased levels of reduced GSH and a concomitant increase of oxidative stress (Abdalla et al, 2005).…”

Section: Gsh and Viral Infectionmentioning

confidence: 99%

Glutathione: new roles in redox signaling for an old antioxidant

2014

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The physiological roles played by the tripeptide glutathione have greatly advanced over the past decades superimposing the research on free radicals, oxidative stress and, more recently, redox signaling. In particular, GSH is involved in nutrient metabolism, antioxidant defense, and regulation of cellular metabolic functions ranging from gene expression, DNA and protein synthesis to signal transduction, cell proliferation and apoptosis. This review will be focused on the role of GSH in cell signaling by analysing the more recent advancements about its capability to modulate nitroxidative stress, autophagy, and viral infection.

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Inhibitory effects of glutathione on dengue virus production

Cited by 43 publications

References 19 publications

Arsenite-induced stress granule formation is inhibited by elevated levels of reduced glutathione in West Nile virus-infected cells

Arsenite-induced stress granule formation is inhibited by elevated levels of reduced glutathione in West Nile virus-infected cells

The Putative Herpes Simplex Virus 1 Chaperone Protein UL32 Modulates Disulfide Bond Formation during Infection

Glutathione: new roles in redox signaling for an old antioxidant

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