The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection

Galindo, Inmaculada; Hernáez, Bruno; Muñoz-Moreno, Raquel; Cuesta-Geijo, Miguel Ángel; Dalmau-Mena, Inmaculada; Alonso, Covadonga

doi:10.1038/cddis.2012.81

Cited by 92 publications

(89 citation statements)

References 44 publications

(57 reference statements)

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“…Reverse transcriptions PCR reactions (RT-PCR) were carried out using the SuperScript One Step RT-PCR (Life Technologies). Unspliced or spliced Xbp-1 mRNA was amplified as described [36]. Amplification of GAPDH mRNA was carried as a control for RNA extraction.…”

Section: Methodsmentioning

confidence: 99%

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

et al. 2013

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Usutu virus (USUV) is an African mosquito-borne flavivirus closely related to West Nile virus and Japanese encephalitis virus, which host range includes mainly mosquitoes and birds, although infections in humans have been also documented, thus warning about USUV as a potential health threat. Circulation of USUV in Africa was documented more than 50 years ago, but it was not until the last decade that it emerged in Europe causing episodes of avian mortality and some human severe cases. Since autophagy is a cellular pathway that can play important roles on different aspects of viral infections and pathogenesis, the possible implication of this pathway in USUV infection has been examined using Vero cells and two viral strains of different origin. USUV infection induced the unfolded protein response, revealed by the splicing of Xbp-1 mRNA. Infection with USUV also stimulated the autophagic process, which was demonstrated by an increase in the cytoplasmic aggregation of microtubule-associated protein 1 light chain 3 (LC3), a marker of autophagosome formation. In addition to this, an increase in the lipidated form of LC3, that is associated with autophagosome formation, was noticed following infection. Pharmacological modulation of the autophagic pathway with the inductor of autophagy rapamycin resulted in an increase in virus yield. On the other hand, treatment with 3-methyladenine or wortmannin, two distinct inhibitors of phosphatidylinositol 3-kinases involved in autophagy, resulted in a decrease in virus yield. These results indicate that USUV virus infection upregulates the cellular autophagic pathway and that drugs that target this pathway can modulate the infection of this virus, thus identifying a potential druggable pathway in USUV-infection.

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Section: Methodsmentioning

confidence: 99%

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

et al. 2013

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“…Activation of the ATF6 branch of UPR has been observed in cells infected by a handful of viruses including HSV-1 (Burnett et al, 2012), African swine fever virus (ASFV) (Galindo et al, 2012), West Nile virus (WNV) (Ambrose and Mackenzie, 2011) and HCV . Although ATF6 has been shown to promote the replication of WNV by suppressing interferon signaling (Ambrose and Mackenzie, 2013), the effect of ATF6 activation on replication of other viruses has not been studied in detail.…”

Section: Activation Of Atf6 Pathway During Coronavirus Infectionmentioning

confidence: 99%

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

2014

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Coronavirus replication is structurally and functionally associated with the endoplasmic reticulum (ER), a major site of protein synthesis, folding, modification and sorting in the eukaryotic cells. Disturbance of ER homeostasis may occur under various physiological or pathological conditions. In response to the ER stress, signaling pathways of the unfolded protein response (UPR) are activated. UPR is mediated by three ER transmembrane sensors, namely the PKR-like ER protein kinase (PERK), the inositol-requiring protein 1 (IRE1) and the activating transcriptional factor 6 (ATF6). UPR facilitates adaptation to ER stress by reversible translation attenuation, enhancement of ER protein folding capacity and activation of ER-associated degradation (ERAD). In cells under prolonged and irremediable ER stress, UPR can also trigger apoptotic cell death. Accumulating evidence has shown that coronavirus infection causes ER stress and induces UPR in the infected cells. UPR is closely associated with a number of major signaling pathways, including autophagy, apoptosis, the mitogen-activated protein (MAP) kinase pathways, innate immunity and pro-inflammatory response. Therefore, studies on the UPR are pivotal in elucidating the complicated issue of coronavirus-host interaction. In this paper, we present the up-to-date knowledge on coronavirus-induced UPR and discuss its potential involvement in regulation of innate immunity and apoptosis.

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“…The primers used were: forward primer: 5 0 -CCTTGTAGTTGAGAACCAGG-3 0 and reverse primer 5 0 -GGGGCTTGGTATATATGTGG-3 0 . Amplification condition included an initial step of 45°C for 30 s, followed by a denaturation step of 94°C for 2 min, 30 cycles of 94°C for 30 s, 55°C for 30 s and 70°C for 30 s (Galindo et al, 2012). PCR products were resolved by electrophoresis in a 2% agarose gel and stained with GoldenView.…”

Section: Rt-pcrmentioning

confidence: 99%

“…ASFV infection triggers ER stress and the unfolded protein response (UPR) in the host cells by inducing ATF6 signaling pathway of the UPR, but not PERK or IRE1 pathway. UPR regulation by ASFV might prevent early apoptosis to facilitate viral replication (Galindo et al, 2012). Tick-borne encephalitis virus infection activates the IRE1 and ATF6 signal pathways (Yu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Triggering unfolded protein response by 2-Deoxy-d-glucose inhibits porcine epidemic diarrhea virus propagation

Wang

Sun

et al. 2014

Antiviral Research

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The unfolded protein response (UPR) is cyto-protective machinery elicited towards an influx of large amount of protein synthesis in the endoplasmic reticulum (ER). Extensive studies suggest that the UPR can also be activated during virus infection. In the present studies, we first evaluated if porcine epidemic diarrhea virus (PEDV) infection activated the UPR pathways. Electron microscopy analysis demonstrated the morphology changes of ER post-PEDV infection. Western blot and real-time PCR identified the differences of UPR genes in response to PEDV infection. The results suggested that PEDV infection induced UPR in Vero cells. Meanwhile, we silenced the expression of PKR-like ER kinase (PERK) by shRNA, we found that the knockdown of PERK increased virus loads in the cells, which was consistent with the result on 4-phenylbutyrate (4-PBA) treatment. We next determined whether 2-Deoxy-d-glucose (2-DG), an ER stress inducer, possessed antiviral activity against PEDV infection. Plaque formation assay, RT-PCR and Western blot analysis suggested that 2-DG might inhibit virus infection by affecting viral protein translation during the early stage of virus infection. Interestingly, we also found that 2-DG treatment could affect virus assembly, which is similar to previous studies on influenza virus. All these results support the therapeutic potential of using 2-DG or glucose/mannose analogs to induce the UPR to block virus replication.

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The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection

Cited by 92 publications

References 44 publications

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

Infection with Usutu Virus Induces an Autophagic Response in Mammalian Cells

Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions

Triggering unfolded protein response by 2-Deoxy-d-glucose inhibits porcine epidemic diarrhea virus propagation

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