Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Peña, José; Harris, Eva

doi:10.1074/jbc.m111.222703

Cited by 168 publications

(236 citation statements)

References 43 publications

(62 reference statements)

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“…While a number of earlier studies reported that WNV and DENV evade eIF2␣-induced host translation shutoff (42,43), our present findings are consistent with a more recent study showing that DENV, WNV, and ZIKV do in fact inhibit host cell translation (34). In ZIKV-infected cells, NS3 and NS4A appear to be important for this process.…”

Section: Discussionsupporting

confidence: 92%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

111

132

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Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2␣ and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication.IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication.

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Section: Discussionsupporting

confidence: 92%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

111

132

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“…Atf6 was previously shown to support Kunjin virus replication by modulating innate immune responses (37). West Nile virus and dengue virus are known to modulate ER stress signals, such as eIF2␣ and PERK expression, in support of viral growth and to modulate apoptotic signaling (34,35). We also found it interesting that our screen exhibited marked increases in both Ero1L-1␣ and PDI expression.…”

Section: Discussionmentioning

confidence: 58%

“…Asyn is known to localize with Rab1 ϩ vesicles, alter ER membrane trafficking, and modulate ER stress signaling (27). Flaviviruses are also known to increase ER stress signaling in support of viral replication and growth (34,35). Since both flaviviruses (e.g., WNV) and alphaviruses (e.g., VEEV) utilize ER-derived membrane systems for virus replication, we analyzed the interactions between WNV and neuronal membrane compartments.…”

Section: Resultsmentioning

confidence: 99%

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

Beatman

Massey

Shives

et al. 2016

J Virol

178

181

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We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10 4.5 infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virusinduced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease. IMPORTANCENeuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alphasynuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS.

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“…The protein folding pathway and the response to ER stress are complex processes with multiple steps. In addition, UPR pathway has been shown to be highly dynamic with distinct kinetic outcomes depending on the input (DuRose et al 2006;Gass et al 2008;Merquiol et al 2011;Pena and Harris, 2011). A mechanistic understanding of this pathway in recombinant cell lines will therefore aid in designing rational metabolic engineering strategies.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of unfolded protein response in recombinant CHO cells

Prashad

Mehra

2014

Cytotechnology

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Genes in the protein secretion pathway have been targeted to increase productivity of monoclonal antibodies in Chinese hamster ovary cells. The results have been highly variable depending on the cell type and the relative amount of recombinant and target proteins. This paper presents a comprehensive study encompassing major components of the protein processing pathway in the endoplasmic reticulum (ER) to elucidate its role in recombinant cells. mRNA profiles of all major ER chaperones and unfolded protein response (UPR) pathway genes are measured at a series of time points in a high-producing cell line under the dynamic environment of a batch culture. An initial increase in IgG heavy chain mRNA levels correlates with an increase in productivity. We observe a parallel increase in the expression levels of majority of chaperones. The chaperone levels continue to increase until the end of the batch culture. In contrast, calreticulin and ERO1-L alpha, two of the lowest expressed genes exhibit transient time profiles, with peak induction on day 3. In response to increased ER stress, both the GCN2/PKR-like ER kinase and inositol-requiring enzyme-1alpha (Ire1a) signalling branch of the UPR are upregulated. Interestingly, spliced X-Box binding protein 1 (XBP1s) transcription factor from Ire1a pathway is detected from the beginning of the batch culture. Comparison with the expression levels in a low producer, show much lower induction at the end of the exponential growth phase. Thus, the unfolded protein response strongly correlates with the magnitude and timing of stress in the course of the batch culture.

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Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

Cited by 168 publications

References 43 publications

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

Dynamics of unfolded protein response in recombinant CHO cells

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