DEV induce autophagy via the endoplasmic reticulum stress related unfolded protein response

Yin, Huan; Zhao, Lili; Jiang, Xinjie; Li, Siqi; Hong, Hao; Chen, Hongyan

doi:10.1371/journal.pone.0189704

Cited by 20 publications

(22 citation statements)

References 32 publications

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“…During ATF6 activation, the full-length protein (90 kDa) is cleaved to release an active 50-kDa variant of ATF6 comprising the N-terminus [37, 38]. To further explore whether TMUV infection induces the ATF6 branch of the UPR, ATF6 expression was detected by western blotting using an antibody against full-length ATF6.…”

Section: Resultsmentioning

confidence: 99%

The unfolded protein response induced by Tembusu virus infection

et al. 2019

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BackgroundTembusu virus (TMUV), classified in the genus Flavivirus, causes reduced egg production and neurological problems in poultry. Flavivirus replication depends on the host endoplasmic reticulum (ER) and induces ER stress that leads to activation of the cellular unfolded protein response (UPR), an important signalling pathway that regulates many biological functions involved in viral pathogenesis and innate immunity. However, the mechanism of TMUV-induced UPR activation remains unclear.ResultsIn this study, we systematically investigated the three UPR pathways in TMUV-infected BHK-21 cells. Our results showed that expression of glucose-related protein 78 (GRP78) and GRP94 was upregulated during the course of TMUV infection. We then demonstrated that TMUV activated the PERK pathway in the early stage of infection, resulting in upregulation of ATF4, GADD34 and CHOP, with CHOP induction leading to caspase-3 activation. We also found the IRE1 pathway to be activated, leading to splicing of X box binding protein 1 (XBP1) mRNA and enhanced expression of p58IPK. Finally, we observed increased expression of ATF6 and activity of ER stress-response elements, suggesting stimulation of the ATF6 pathway. In addition, ATF6 pathway activation correlated with the induction of downstream chaperones calnexin, calreticulin, ERp57 and PDI. UPR activity was also observed by the marked elevation in GRP78 and sXBP1 levels in TMUV-infected DF-1 cells.ConclusionsThis is the first report that TMUV infection-induced ER stress activates three branches of the UPR, and these results lay the foundation for elucidating the pathogenesis of TMUV and understanding the inherent mechanism of TMUV infection as well as the host response.

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Section: Resultsmentioning

confidence: 99%

The unfolded protein response induced by Tembusu virus infection

et al. 2019

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“…In addition to PERK, the other two ER membrane-associated proteins that activate the UPR were ATF6 ( Figure 6D ) and IRE1, and the latter promotes the phosphorylation of JNK, P38, and NF-κB kinase ( Figure 6B ). However, pretreatment with ATV disturbed the activation of chaperones such as Grp78/Bip dissociation from IRE1-α, PERK, and ATF6 during acute ER stress ( Yin et al, 2017 ), as well as calnexin, Nrf2 and Ero1-Lα, which participate in oxidative and Ca 2+ -related stress to regulate ER stress ( Giorgi et al, 2015 ) ( Figure 6C ), and downregulated the downstream activation of JNK, P38 and NF-κB kinase ( Figure 6B ) to inhibit the subsequent apoptosis ( Ma et al, 2017 ). Furthermore, there was no significance in the change in Ero1-Lα between the vehicle PMCAO and AMCAO groups ( Figure 6C ).…”

Section: Resultsmentioning

confidence: 99%

HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia

Zhang

Yang

et al. 2018

Front. Neurosci.

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Exploring and expanding the indications of common clinical drugs, such as statins, is important to improve the prognosis of patients with permanent cerebral infarction. It has been suggested that reversing the defects in cellular autophagy and ER stress with statin therapy may be a potential treatment option for reducing ischemic damage. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO) by electrocoagulation surgery. Atorvastatin (ATV, 10 mg/kg/day) or vehicle was administered intraperitoneally. Rats were divided into the vehicle-treated (SHAM), ATV pretreatment for MCAO (AMCAO), and 3-methyladenine (3MA) combined with ATV pretreatment (3MAMCAO) groups. Magnetic resonance imaging, as well as immunohistochemical and Western blot assessments, were performed 24 h after MCAO. Each ATV-treated group demonstrated significant reductions in infarct volume compared with that in the vehicle-treated group at 24 h after MCAO, which was associated with autophagy reduction and ER stress attenuation in neurons and neovascularization. Next, Western blotting was used to detect the levels of the autophagy-related proteins LC3B and P62 and of ER stress pathway proteins. However, 3MA significantly partially inhibited the ER stress pathway via limiting the autophagic flux in the AMCAO group. In conclusion, our results imply that the neuroprotective function of ATV depends on autophagic activity to diminish ER stress-related cell apoptosis in rats with PMCAO and suggest that compounds that inhibit autophagic activity might reduce the neuroprotective effect of ATV after brain ischemia.

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“…Finally, we would like to point out papers that describe enhanced autophagy following infection with two other alpha herpes viruses: PRV and duck enteritis herpes virus (Yin H. et al, 2017; Yin H.C. et al, 2017; Xu et al, 2018). The data within these manuscripts were mutually supportive, for example, the similarities between innate immunity in response to VZV and PRV infection (Jarosinski et al, 2018; Laval et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Quantification and STAT3 Expression in a Human Skin Organ Culture Model for Innate Immunity to Herpes Zoster

et al. 2018

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The goal of this project was to document the autophagy response in human neonatal skin organ culture (SOC) after infection with varicella-zoster virus (VZV). The VZV-infected SOC model has attributes of herpes zoster, in that an injection of virus into the skin is analogous to exit of virus from the sensory nerve termini into skin during herpes zoster. Cultures were maintained for 28 days and periodically examined for an autophagy response by quantitation of autophagosomes with Imaris software. Expression of the STAT3 protein was plentiful in the VZV-infected SOC. Abundant autophagy was observed in VZV-infected SOC between 14 and 28 days after infection, while autophagy in mock-infected SOC was minimal (p = 0.0003). The autophagic response after infection of SOC with a recombinant VZV genome containing the herpes simplex virus ICP34.5 neurovirulence gene was similar to wild-type VZV (p = 0.3). These results suggested that the VZV-infected SOC system resembled biopsy data from herpes zoster infection of skin. An enhanced autophagy response has now been reported after infection with two additional alpha herpesviruses besides VZV, namely, pseudorabies virus and duck enteritis herpes virus; both lack the ICP34.5 protein.

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DEV induce autophagy via the endoplasmic reticulum stress related unfolded protein response

Cited by 20 publications

References 32 publications

The unfolded protein response induced by Tembusu virus infection

The unfolded protein response induced by Tembusu virus infection

HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia

Autophagy Quantification and STAT3 Expression in a Human Skin Organ Culture Model for Innate Immunity to Herpes Zoster

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