Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress

Lee, Junsub; Koh, Kyungmi; Kim, Young-Eui; Ahn, Jin-Hyun; Kim, Sun‐Young

doi:10.1099/vir.0.052142-0

Cited by 48 publications

(48 citation statements)

References 40 publications

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“…These findings are in partially agreement with previous studies in adults [29,30,62], showing that increased levels of OS were associated with CMV infection [29]. These studies have also indicated that OS may importantly drive the CMV reactivation and replication [28,30].…”

Section: Discussionsupporting

confidence: 92%

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging

Müller

Gottlieb

Correa

et al. 2015

Cellular Immunology

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Aging has been associated with increased generation of free radicals as well as immunosenescence. Previous studies have identified older individuals with inverted T CD4:CD8 cell ratio and increased immunity to cytomegalovirus (CMV). Here, we investigated markers of oxidative stress and antioxidant defences in older individuals with inverted CD4:CD8 T-cell ratio. Sixty-one subjects were identified with inverted CD4:CD8 ratio. Older individuals with a CD4:CD8 ratio <1 had increased levels of plasma advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP), but reduced levels of thiobarbituric acid reactive substances (TBARS) as compared to subjects with normal CD4:CD8 ratio. The CMV IgG serology was negatively correlated with CD4:CD8 ratio. These markers were more evident among elderly men than women. Our data suggest a close relationship between chronic CMV infection and oxidative profile in older individuals in the midst of its influence on the peripheral T-cell subsets.

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Section: Discussionsupporting

confidence: 92%

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging

Müller

Gottlieb

Correa

et al. 2015

Cellular Immunology

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“…In addition, infection of human foreskin fibroblasts with human cytomegalovirus (HCMV/HHV-5) led to the activation of Nrf2 (81). While a previous study reported that HCMV infection led to an increased level of ROS, Nrf2 activation was not mediated by oxidative stress but was rather due to HCMV gene expression (81,82). Finally, Marburg virus was shown to hijack the Nrf2 pathway through its protein VP-24 (83,84).…”

Section: Discussionmentioning

confidence: 95%

“…HCV activation of Nrf2 was dependent on both oxidative stress and calcium responses (79); 5 distinct HCV proteins (core protein, E1, E2, NS4B, and NS5A) activated Nrf2, and this activation was only partially dependent on ROS production (80). In addition, infection of human foreskin fibroblasts with human cytomegalovirus (HCMV/HHV-5) led to the activation of Nrf2 (81). While a previous study reported that HCMV infection led to an increased level of ROS, Nrf2 activation was not mediated by oxidative stress but was rather due to HCMV gene expression (81,82).…”

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Gjyshi

Flaherty

Veettil

et al. 2015

J Virol

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Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term-infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase C (PKC) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (␥GCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2-mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCEThe transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQS...

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“…Targeting Nrf2 signaling seems to improve bacterial clearance by alveolar macrophages in patients with chronic obstructive pulmonary disease as well as in a mouse model of P. aeruginosa or nontypeable Haemophilus influenzae (52). For several viruses, the Nrf2-mediated induction of cytoprotective genes has been considered to protect infected cells from oxidative damage (53)(54)(55)(56). A recent study described the direct interaction of a Marburg virus protein with the Nrf2 inhibitor Kelch-like ECHassociated protein 1 to activate the cytoprotective antioxidant response pathway as part of their replication strategy (57).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Stolt

Schmidt

Sayfart

et al. 2016

The Journal of Immunology

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The environmental bacterium and potential biothreat agent Burkholderia pseudomallei causes melioidosis, an often fatal infectious disease. Increased serum bilirubin has been shown to be a negative predictive factor in melioidosis patients. We therefore investigated the role of heme oxygenase-1 (HO-1), which catalyzes the degradation of heme into the bilirubin precursor biliverdin, ferrous iron, and CO during B. pseudomallei infection. We found that infection of murine macrophages induces HO-1 expression, involving activation of several protein kinases and the transcription factor nuclear erythroid-related factor 2 (Nrf2). Deficiency of Nrf2 improved B. pseudomallei clearance by macrophages, whereas Nrf2 activation by sulforaphane and tert-butylhydroquinone with subsequent HO-1 induction enhanced intracellular bacterial growth. The HO-1 inducer cobalt protoporphyrin IX diminished proinflammatory cytokine levels, leading to an increased bacterial burden in macrophages. In contrast, HO-1 gene knockdown reduced the survival of intramacrophage B. pseudomallei. Pharmacological administration of cobalt protoporphyrin IX to mice resulted in an enhanced bacterial load in various organs and was associated with higher mortality of intranasally infected mice. The unfavorable outcome of B. pseudomallei infection after HO-1 induction was associated with higher serum IL-6, TNF-α, and MCP-1 levels but decreased secretion of IFN-γ. Finally, we demonstrate that the CO-releasing molecule CORM-2 increases the B. pseudomallei load in macrophages and mice. Thus, our data suggest that the B. pseudomallei–mediated induction of HO-1 and the release of its metabolite CO impair bacterial clearance in macrophages and during murine melioidosis.

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Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress

Cited by 48 publications

References 40 publications

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging

The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

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