Virus-induced ER stress and the unfolded protein response

Zhang, Lingrui; Wang, Aiming

doi:10.3389/fpls.2012.00293

Cited by 135 publications

(131 citation statements)

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“…Our experiments with wt and SAT Ϫ viruses revealed that PPV, similarly to numerous other viruses from different viral families (50)(51)(52)(53)(54), induces ER stress and UPR in infected cells, as demonstrated by the morphological changes of the ER and expression of Xbp1 and CHOP (55). It is suspected that the different localization of CHOP depends on the state of the cells and the intensity of the stress effect (56).…”

Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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The SAT protein (SATp) of porcine parvovirus (PPV) accumulates in the endoplasmic reticulum (ER), and SAT deletion induces the slow-spreading phenotype. The in vitro comparison of the wild-type Kresse strain and its SAT knockout (SAT Ϫ ) mutant revealed that prolonged cell integrity and late viral release are responsible for the slower spreading of the SAT Ϫ virus. During PPV infection, regardless of the presence or absence of SATp, the expression of downstream ER stress response proteins (Xbp1 and CHOP) was induced. However, in the absence of SATp, significant differences in the quantity and the localization of CHOP were detected, suggesting a role of SATp in the induction of irreversible ER stress in infected cells. The involvement of the induction of irreversible ER stress in porcine testis (PT) cell necrosis and viral egress was confirmed by treatment of infected cells by ER stressinducing chemicals (MG132, dithiothreitol, and thapsigargin), which accelerated the egress and spreading of both the wild-type and the SAT Ϫ viruses. UV stress induction had no beneficial effect on PPV infection, underscoring the specificity of ER stress pathways in the process. However, induction of CHOP and its nuclear translocation cannot alone be responsible for the biological effect of SAT, since nuclear CHOP could not complement the lack of SAT in a coexpression experiment. IMPORTANCE SATp is encoded by an alternative open reading frame of the PPV genome. Earlier we showed that SATp of the attenuated PPV NADL-2 strain accumulates in the ER and accelerates virus release and spreading. Our present work revealed that slow spreading is a general feature of SAT Ϫ PPVs and is the consequence of prolonged cell integrity. PPV infection induced ER stress in infected cells regardless of the presence of SATp, as demonstrated by the morphological changes of the ER and expression of the stress response proteins Xbp1 and CHOP. However, the presence of SATp made the ER stress more severe and accelerated cell death during infection, as shown by the higher rate of expression of CHOP and alteration of the localization of CHOP. The beneficial effect of irreversible ER stress on PPV spread was confirmed by treatment of infected cells with ER stress-inducing chemicals.KEYWORDS CHOP, ER stress, SAT, Xbp1, alternative ORF, parvovirus, protoparvovirus, viral egress P orcine parvovirus (PPV) belongs to the species Ungulate protoparvovirus 1 in the genus Protoparvovirus. It is the causative agent of the stillbirth, mummification, embryonic death, infertility (SMEDI) syndrome in swine (1).A highly pathogenic strain with broad tissue tropism, strain Kresse, was isolated in the 1980s (2, 3). Kresse strain-infected piglets showed atypical signs of PPV infection, including necrotic lesions (4) on the lips, snout, tongue, and foot.The PPV single-stranded genome contains two major open reading frames (ORFs)

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Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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“…43 Cancer cell infection with oncolytic viruses produce large amounts of viral proteins, which inevitably cause ER stress and ROS production to promote viral replication. 44,45 The quality and/or quantity of ER stress linking ROS triggered by ICD inducers may determine the ICD properties. Indeed, the previous finding that rigorous ROS-mediated ER stress augmented the release of DAMPs revealed an unrecognized role of RNA-dependent protein kinase (PKR)-like ER kinase (PERK) as a constituent of mitochondria-associated ER membranes to exert ROS-mediated mitochondrial apoptosis.…”

Section: Icd Inducersmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

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“…Although the reason for this disconnect between in vitro and in vivo observations is not overtly apparent, we realize that cultured cells represent an isolated system that has metabolic properties that may be very different from hepatocytes in vivo because of the presence of biochemical and physiologic feedback loops in a living organism. The presence of protein in the absence of activity suggests that the virus induces a unique set of conditions that create a stable, yet inactive, form of the protein similar to what has been observed in cases of virus-induced stress and the unfolded protein response (Hetz, 2012;Zhang and Wang, 2012). This response is very sensitive to the amount of virus in contact with the cell.…”

Section: Hc-04 Cells As An In Vitro Model For Hepatic Metabolism 1197mentioning

confidence: 87%

Evaluation of the HC-04 Cell Line as an In Vitro Model for Mechanistic Assessment of Changes in Hepatic Cytochrome P450 3A during Adenovirus Infection

et al. 2014

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HC-04 cells were evaluated as an in vitro model for mechanistic study of changes in the function of hepatic CYP3A during virus infection. Similar to in vivo observations, infection with a first generation recombinant adenovirus significantly inhibited CYP3A4 catalytic activity in an isoform-specific manner. Virus (MOI 100) significantly reduced expression of the retinoid X receptor (RXR) by 30% 96 hours after infection. Cytoplasmic concentrations of the pregnane X receptor (PXR) were reduced by 50%, whereas the amount of the constitutive androstane receptor (CAR) in the nuclear fraction doubled with respect to uninfected controls. Hepatocyte nuclear factor 4a (HNF-4a) and peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) were also reduced by ∼70% during infection. Virus suppressed CYP3A4 activity in the presence of the PXR agonist rifampicin and did not affect CYP3A4 activity in the presence of the CAR agonist CITCO [6-(4-chlorophenyl) imidazosuggesting that virus-induced modification of PXR may be responsible for observed changes in hepatic CYP3A4. The HC-04 cell line is easy to maintain, and CYP3A4 in these cells was responsive to known inducers and suppressors. Dexamethasone (200 mM) and phenobarbital (500 mM) increased activity by 230 and 124%, whereas ketoconazole (10 mM) and lipopolysaccharide (LPS) (10 mg/ml) reduced activity by 90 and 92%, respectively. This suggests that HC-04 cells can be a valuable tool for mechanistic study of drug metabolism during infection and for routine toxicological screening of novel compounds prior to use in the clinic.

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Virus-induced ER stress and the unfolded protein response

Cited by 135 publications

References 143 publications

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Evaluation of the HC-04 Cell Line as an In Vitro Model for Mechanistic Assessment of Changes in Hepatic Cytochrome P450 3A during Adenovirus Infection

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