Respiratory Syncytial Virus Infection Induces Expression of the Anti‐Apoptosis Gene<i>IEX‐1L</i>in Human Respiratory Epithelial Cells

Domachowske, Joseph B.; Bonville, Cynthia A.; Mortelliti, Anthony J.; Colella, Carol B.; Kim, Urian; Rosenberg, Helene F.

doi:10.1086/315319

Cited by 46 publications

(47 citation statements)

References 24 publications

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“…Interestingly, it has been reported that human RS virus, which does not encode a V protein, induces expression of GRP 78 (a major indicator of ER stress in A549 cells) and causes cell death (6). However, there are other reports indicating that infection by RS virus does not induce apoptosis (11,50). It has been reported that mutant SV5 containing mutations in the shared N termini of V and P protein (known as CPIϪ virus) accelerates viral gene expression and causes increased cell death, with characteristics of apoptosis (60).…”

Section: Vol 78 2004 Paramyxovirus V Protein and Apoptosis 5075mentioning

confidence: 99%

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Sun¹,

Rothermel²,

Shuman³

et al. 2004

J Virol

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The paramyxovirus family includes many well-known human and animal pathogens as well as emerging viruses such as Hendra virus and Nipah virus. The V protein of simian virus 5 (SV5), a prototype of the paramyxoviruses, contains a cysteine-rich C-terminal domain which is conserved among all paramyxovirus V proteins. The V protein can block both interferon (IFN) signaling by causing degradation of STAT1 and IFN production by blocking IRF-3 nuclear import. Previously, it was reported that recombinant SV5 lacking the C terminus of the V protein (rSV5V⌬C) induces a severe cytopathic effect (CPE) in tissue culture whereas wild-type (wt) SV5 infection does not induce CPE. In this study, the nature of the CPE and the mechanism of the induction of CPE were investigated. Through the use of DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, and propidium iodide staining assays, it was shown that rSV5V⌬C induced apoptosis. Expression of wt V protein prevented apoptosis induced by rSV5V⌬C, suggesting that the V protein has an antiapoptotic function. Interestingly, rSV5V⌬C induced apoptosis in U3A cells (a STAT1-deficient cell line) and in the presence of neutralizing antibody against IFN, suggesting that the induction of apoptosis by rSV5V⌬C was independent of IFN and IFN-signaling pathways. Apoptosis induced by rSV5V⌬C was blocked by a general caspase inhibitor, Z-VAD-FMK, but not by specific inhibitors against caspases 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 13, suggesting that rSV5V⌬C-induced apoptosis can occur in a caspase 12-dependent manner. Endoplasmic reticulum stress can lead to activation of caspase 12; compared to the results seen with mock and wt SV5 infection, rSV5V⌬C infection induced ER stress, as demonstrated by increased expression levels of known ER stress indicators GRP 78, GRP 94, and GADD153. These data suggest that rSV5V⌬C can trigger cell death by inducing ER stress.

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Section: Vol 78 2004 Paramyxovirus V Protein and Apoptosis 5075mentioning

confidence: 99%

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Sun¹,

Rothermel²,

Shuman³

et al. 2004

J Virol

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“…Bcl2 and p53 binding protein (BBP/53BP2) is a DNA damage-inducible protein which functions to promote apoptosis upon DNA damage (25,26). IEX-1L antideath protein has been recognized as an apoptosis inhibitor involved in NF-B-mediated cell survival (15,16). In contrast, a proapoptotic role of IEX-1 has also been presented (17)(18)(19).…”

Section: Expression Profiling Of Tnf-␣-modulated Nf-b-dependent Genesmentioning

confidence: 99%

“…Among several NF-B-dependent genes, we focused on x-ray-inducible immediate early response factor-1 (IEX-1), which is a unique immediate-early gene that was initially identified following exposure of human squamous carcinoma cells to X-irradiation (14). Recent studies indicate that IEX-1 is implicated in apoptotic signaling and cell cycle control (15)(16)(17)(18)(19)(20)(21)(22). However, IEX-1 appears to exert apparently contradictory effects, depending on the type of cells, stimuli, and its expressed forms.…”

mentioning

confidence: 99%

“…However, IEX-1 appears to exert apparently contradictory effects, depending on the type of cells, stimuli, and its expressed forms. For example, the longer IEX-1 transcript with 37 amino acid insertion, called IEX-1L, is regarded as an apoptosis inhibitor in NF-B-mediated cell survival (15,16), whereas IEX-1S, a shorter original IEX-1 transcript promotes apoptosis (17,18,19). Interestingly, it has been proposed by two independent investigators that IEX-1S may promote cell proliferation under favorable growth conditions but facilitate apoptosis under unfavorable conditions (17,18).…”

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confidence: 99%

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Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.

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“…Similarly, RSV infection of HEp‐2 cells induces the antiapoptotic factor IEX‐1L (Domachowske et al. 2000), and inhibition of phosphatidylinositol‐3‐kinase (PI3K) results in more rapid apoptosis via the NF‐ κ B pathway (Thomas et al. 2002).…”

Section: Discussionmentioning

confidence: 99%

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy

et al. 2017

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Cytotoxic and neuroinflammatory effects of TiO2 nanoparticles (TiO2‐NP) in human airways are mediated by nerve growth factor (NGF), which is also implicated in the pathophysiology of respiratory syncytial virus (RSV) infection. We tested the hypothesis that exposure to TiO2‐NP results in increased susceptibility to RSV infection and exacerbation of airway inflammation via NGF‐mediated induction of autophagy in lower respiratory tract cells. Human primary bronchial epithelial cells were exposed to TiO2‐NP for 24 h prior to infection with recombinant red RSV (rrRSV). Expression of NGF and its TrkA and p75NTR receptors was measured by real‐time PCR and fluorescence‐activated cell sorting (FACS). Autophagy was assessed by beclin‐1 expression analysis. Cell death was studied by FACS after annexin V/propidium iodide staining. rrRSV infection efficiency more than doubled in human bronchial cells pre‐exposed to TiO2‐NP compared to controls. NGF and its TrkA receptor were upregulated in RSV‐infected bronchial cells pre‐exposed to TiO2‐NP compared to controls exposed to either rrRSV or TiO2‐NP alone. Silencing NGF gene expression with siRNA significantly inhibited rrRSV infection. rrRSV‐infected cells pre‐exposed to TiO2‐NP also showed increase in necrotic cell death and reduction in apoptosis, together with 4.3‐fold increase in expression of the early autophagosomal gene beclin‐1. Pharmacological inhibition of beclin‐1 by wortmannin resulted in increased apoptotic rate along with lower viral load. This study shows that TiO2‐NP exposure enhances the infectivity of RSV in human bronchial epithelial cells by upregulating the NGF/TrkA axis. The mechanism of this interaction involves induction of autophagy promoting viral replication and necrotic cell death.

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Respiratory Syncytial Virus Infection Induces Expression of the Anti‐Apoptosis GeneIEX‐1Lin Human Respiratory Epithelial Cells

Cited by 46 publications

References 24 publications

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy

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