IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells

Qi, Yongfen; Li, Ying; Zhang, Yingke; Zhang, Lin; Wang, Zilian; Zhang, Xuzhi; Gui, Lian; Huang, Junqi

doi:10.1371/journal.pone.0132743

Cited by 57 publications

(59 citation statements)

References 36 publications

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“…P-triflouromethoxyphenylhydrazone (FCCP) transports protons across mitochondrial inner membranes and induces the depolarization of mitochondria potential (49). Consistent with previous studies (46)(47)(48), our results also suggest that IFI6-16 stabilizes the mitochondrial membrane potential, as shown by residual TMRM fluorescence signal even in cells treated with a low FCCP dose for 10 min (Fig. 6).…”

Section: P7 and Ifi6-16 Counteract By Regulating The Mitochondrial Mesupporting

confidence: 91%

“…However, little was known about its function or the mechanism in blocking viral infection. Recent studies suggest that IFI6-16 plays a critical role in stabilizing cancer cells by inhibiting mitochondrial-mediated apoptosis (46,47), and it also regulates apoptosis in Dengue virus (DENV)-infected cells (48). To examine whether p7 counteracts with IFI6-16 to regulate the mitochondrial function, we performed a mitochondrial membrane potential (Δψ) assay using a well-characterized potentiometric fluorescent dye, tetramethylrhodamine methyl ester (TMRM).…”

Section: P7 and Ifi6-16 Counteract By Regulating The Mitochondrial Mementioning

confidence: 99%

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Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to downregulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.HCV | innate immune evasion mechanism | IF6-16 antiviral function | high-throughput mutagenesis | p7 ion channel protein W ith an estimated 170 million people persistently infected worldwide, hepatitis C virus (HCV) has emerged as a major cause of human liver diseases, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1, 2). Despite the recent breakthroughs in the development of HCV direct antiviral agents (DAAs) aiming to cure chronic HCV infection, emerging resistant mutations and drug-resistant polymorphisms at the baseline of treatments remain major challenges to eradicate HCV (3-8). In addition, the high cost of these DAAs limits their accessibility to the majority of patients worldwide. Therefore, HCV eradication is still heavily dependent on the development of an effective preventative vaccine (9). Understanding how the virus evades the immune system, which results in a poor immune response of the infected host against the virus, will provide important information for immune therapy and vaccine development.

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Section: P7 and Ifi6-16 Counteract By Regulating The Mitochondrial Mesupporting

confidence: 91%

Section: P7 and Ifi6-16 Counteract By Regulating The Mitochondrial Mementioning

confidence: 99%

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…We identified two genes that were highly up-regulated in IFN-b-treated DAOY cells, in the absence or presence of TBEV, IFI6 and IFI27. They belong to the FAM14 family of ISGs [72] and were documented as mitochondrial proteins involved in apoptosis regulation [73][74][75]. Over-expression of IFI6 inhibited DENV-induced apoptosis of endothelial cells [74,75] and restricted HCV replication in hepatocarcinoma cells [76].…”

Section: Discussionmentioning

confidence: 99%

Analysis of tick-borne encephalitis virus-induced host responses in human cells of neuronal origin and interferon-mediated protection

Selinger

Wilkie

Tong

et al. 2017

Journal of General Virology

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Tick-borne encephalitis virus (TBEV) is a member of the genus Flavivirus. It can cause serious infections in humans that may result in encephalitis/meningoencephalitis. Although several studies have described the involvement of specific genes in the host response to TBEV infection in the central nervous system (CNS), the overall network remains poorly characterized. Therefore, we investigated the response of DAOY cells (human medulloblastoma cells derived from cerebellar neurons) to TBEV (Neudoerfl strain, Western subtype) infection to characterize differentially expressed genes by transcriptome analysis. Our results revealed a wide panel of interferon-stimulated genes (ISGs) and pro-inflammatory cytokines, including type III but not type I (or II) interferons (IFNs), which are activated upon TBEV infection, as well as a number of non-coding RNAs, including long non-coding RNAs. To obtain a broader view of the pathways responsible for eliciting an antiviral state in DAOY cells we examined the effect of type I and III IFNs and found that only type I IFN pretreatment inhibited TBEV production. The cellular response to TBEV showed only partial overlap with gene expression changes induced by IFN-b treatment -suggesting a virus-specific signature -and we identified a group of ISGs that were highly up-regulated following IFN-b treatment. Moreover, a high rate of down-regulation was observed for a wide panel of pro-inflammatory cytokines upon IFN-b treatment. These data can serve as the basis for further studies of host-TBEV interactions and the identification of ISGs and/or lncRNAs with potent antiviral effects in cases of TBEV infection in human neuronal cells.

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“…IFI27 family members have been suggested to localize to the mitochondria (21,22) or to the nuclear membrane (23,24); in the latter case, IFI27 interacts with and sequesters the NR4A1 nuclear receptor, which regulates expression of anti-inflammatory genes (24). IFI27 family members also appear to have proapoptotic effects (21,32,34,65,66), possibly as a result of stabilization of the mitochondrial membrane and regulation of caspase activity (21,65). Perhaps because of these proposed pleotropic activities, IFI27 family members have been associated with overexpression in certain cancers (66,67), promotion of skin keratinocyte replication (68), and DNA damage-induced apoptosis and cytochrome c release (21).…”

Section: Discussionmentioning

confidence: 99%

“…IFI6-16 (IFI6) is an ISG12 motifcontaining family member that may share some functions with Ifi27l2a. In the context of DENV infection, a deficiency of IFI6-16 was associated with increased caspase levels and decreased Bcl-2 expression and mitochondrial membrane stabilization (65). Additionally, ectopic expression of IFI6-16 has been shown to suppress infection of YFV (69).…”

Section: Discussionmentioning

confidence: 99%

The Interferon-Stimulated Gene Ifi27l2a Restricts West Nile Virus Infection and Pathogenesis in a Cell-Type- and Region-Specific Manner

Lucas

Richner

Diamond

2016

J Virol

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The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs).While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified Ifi27l2a as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated Ifi27l2a ؊/؊ mice. Although adult mice lacking Ifi27l2a were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that Ifi27l2a ؊/؊ cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-␤) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues. IMPORTANCEThe interferon-stimulated Ifi27l2a gene is expressed differentially within the central nervous system upon interferon stimulation or viral infection. Prior studies in cell culture suggested an antiviral role for Ifi27l2a during infection by West Nile virus (WNV). To characterize its antiviral activity in vivo, we generated mice with a targeted gene deletion of Ifi27l2a. Based on extensive virological analyses, we determined that Ifi27l2a protects mice from WNV-induced mortality by contributing to the control of infection of the hindbrain and spinal cord, possibly by regulating cell death of neurons. This antiviral activity was validated in granule cell neurons derived from the cerebellum and in macrophages but was not observed in other cell types. Collectively, these data suggest that Ifi27l2a contributes to innate immune restriction of WNV in a cell-type-and tissue-specific manner. , dengue virus [DENV] and yellow fever virus [YFV]). WNV transmission occurs betweenCulex species mosquitoes and selected avian hosts, with incidental, dead-end infection of horses, humans, and other vertebrate animals. Humans can develop severe disease following WNV infection, as the virus can invade the central nervous system (CNS) and cause flaccid paralysis, meningitis, or encephalitis, often leading to long-term neurological sequelae or death (1)...

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IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells

Cited by 57 publications

References 36 publications

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein

Analysis of tick-borne encephalitis virus-induced host responses in human cells of neuronal origin and interferon-mediated protection

The Interferon-Stimulated Gene Ifi27l2a Restricts West Nile Virus Infection and Pathogenesis in a Cell-Type- and Region-Specific Manner

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