The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly

Alfano, Christian; Gladwyn-Ng, Ivan; Couderc, Thérèse; Lecuit, Marc; Nguyen, Laurent

doi:10.3389/fncel.2019.00094

Cited by 29 publications

(35 citation statements)

References 99 publications

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“…The lack of a phenotype following drug treatment may indicate that UPR pathways do not affect ZIKV infection in A549 cells. This is in contrast to some studies that have linked ZIKV infection to the induction of the UPR in human fetal microcephalic cortices [29]. Here, the activation of the UPR is believed to impair corticogenesis and neurogenesis, a phenotype that was reversed with the addition of UPR inhibitors.…”

Section: Discussioncontrasting

confidence: 67%

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Glucose-Regulated Protein 78 Interacts with Zika Virus Envelope Protein and Contributes to a Productive Infection

Royle

Ramírez-Santana

Akpunarlieva

et al. 2020

Viruses

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Zika virus (ZIKV; Flaviviridae) is a mosquito-borne flavivirus shown to cause fetal abnormalities collectively known as congenital Zika syndrome and Guillain-Barré syndrome in recent outbreaks. Currently, there is no specific treatment or vaccine available, and more effort is needed to identify cellular factors in the viral life cycle. Here, we investigated interactors of ZIKV envelope (E) protein by combining protein pull-down with mass spectrometry. We found that E interacts with the endoplasmic reticulum (ER) resident chaperone, glucose regulated protein 78 (GRP78). Although other flaviviruses are known to co-opt ER resident proteins, including GRP78, to enhance viral infectivity, the role ER proteins play during the ZIKV life cycle is yet to be elucidated. We showed that GRP78 levels increased during ZIKV infection and localised to sites coincident with ZIKV E staining. Depletion of GRP78 using specific siRNAs significantly reduced reporter-virus luciferase readings, viral protein synthesis, and viral titres. Additionally, GRP78 depletion reduced the ability of ZIKV to disrupt host cell translation and altered the localisation of viral replication factories, though there was no effect on viral RNA synthesis. In summary, we showed GRP78 is a vital host-factor during ZIKV infection, which may be involved in the coordination of viral replication factories.

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Section: Discussioncontrasting

confidence: 67%

“…UPR proteins, including GRP78, may be important during ZIKV infection. Activation of this pathway has been linked to clinical features of ZIKV infection such as microcephaly [29]. Additionally, ZIKV has been shown to upregulate the production of UPR proteins, including GRP78, during infection of neural cell culture [30].…”

Section: Introductionmentioning

confidence: 99%

Glucose-Regulated Protein 78 Interacts with Zika Virus Envelope Protein and Contributes to a Productive Infection

Royle

Ramírez-Santana

Akpunarlieva

et al. 2020

Viruses

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“…During the unfolded protein response, GRP78 (also known as HSPA5) releases IRE-1 a [70]. Consistent with studies investigating the unfolded protein response during ZIKV infection [71][72][73], we observed an upregulation of two genes within the unfolded protein response pathway (HSPA5 and XBP1) in ZIKV PR -infected SH-SY5Y cells ( Figure 3B and Figure S2).…”

Section: Discussionsupporting

confidence: 88%

Asian Zika virus isolate significantly changes the transcriptional profile and alternative RNA splicing events in a neuroblastoma cell line

Bonenfant

Meng

Shotwell

et al. 2019

Preprint

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Alternative splicing of pre-mRNAs expands a single genetic blueprint to encode multiple functionally diverse protein isoforms. Viruses have previously been shown to interact with, depend on, and alter host splicing machinery. The consequences however incited by viral infection on the global alternative slicing (AS) landscape are under appreciated. Here we investigated the transcriptional and alternative splicing profile of neuronal cells infected with a contemporary Puerto Rican Zika virus (ZIKV PR ) isolate, the prototypical Ugandan ZIKV (ZIKV MR ) isolate and dengue virus 2 (DENV2). Our analyses revealed that ZIKV PR induced significantly more differential changes in expressed genes compared to ZIKV MR or DENV2, despite all three viruses showing equivalent infectivity and viral RNA levels. Consistent with the transcriptional profile, ZIKV PR induced a higher number of alternative splicing events compared to ZIKV MR or DENV2, and gene ontology analyses highlighted alternative splicing changes in genes associated with mRNA splicing. All three viruses modulated alternative splicing with ZIKV PR having the largest impact on splicing. ZIKV alteration of the transcriptomic landscape during infection caused changes in cellular RNA homeostasis, which might dysregulate neurodevelopment and function leading to neuropathologies such as microcephaly and Guillain-Barré syndrome associated with the ZIKV infection. IntroductionZika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that is classified within the Flaviviridae family. Other notable flaviviruses include Dengue virus (DENV), Yellow Fever virus (YFV), West Nile virus (WNV) and Tick-borne encephalitis virus, all of which are primarily transmitted via the bite of an infected mosquito or tick [1]. Flavivirus infections rarely result in death and common symptoms include maculopapular rash, fever, and achy joints [2]. Until the early 2000s, only 13 confirmed ZIKV infections in humans were reported [3-6]. The first major outbreak of ZIKV occurred in 2007 on Yap Island [7], followed by a 2010 outbreak in Cambodia [8], and an outbreak in French Polynesia in 2013 which resulted in more than 29,000 human infections [9]. This Asian lineage of ZIKV expanded west and in 2015 efforts were redirected towards understanding the link between ZIKV infection and the associated neurological pathologies that are now termed Congenital Zika Syndrome (CZS) [10,11]. To date there are no antivirals or a licensed vaccine to prevent ZIKV infection. Therefore, to develop effective therapies and thus limit the dreadful symptoms associated with ZIKV infection it is critical to understand viral-host interactions and ZIKV pathogenesis.The striking feature of the recent ZIKV outbreak in the America's was the correlation between intrauterine ZIKV infection and the devastating consequences to fetal brain development resulting in microcephaly, cortical malformations and intracranial calcifications [12][13][14][15] and the increased number of cases of Guillain-Barré syndrome in adults [16][17][18][...

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“…This important protein processing can potentially cause ER stress. It has previously been shown that ZIKV has the ability to instruct an UPR in response to ER stress [12][13][14][15][16] and that infection is accompanied by morphological modification of cell organelles [17].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk Between Endoplasmic Reticulum Stress and The Unfolded Protein Response During ZIKA Virus Infection

Turpin¹,

Frumence²,

Harrabi³

et al. 2019

Preprint

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Flaviviruses replicate in membranous factories associated with the endoplasmic reticulum (ER). The replication rate generates a high polyprotein integration that can contribute to ER stress. Therefore, the host cell can develop an Unfolded Protein Response (UPR) to this protein accumulation which will stimulate appropriate cellular responses in the infectious context (Adaptation, autophagy or cell death). These different stress responses can help to overcome the virus and usually support antiviral strategies initiated by infected cells. In the present study, we investigated the capacity of ZIKA virus (ZIKV) to induce ER stress in epithelial A549 cells with a special focus on the causal factors behind it. We observed that the cells respond to ZIKV infection by implementing an UPR through activation of the IRE1 and PERK pathway but surprisingly without activation of the ATF6 branch. When we examined the effects of modulating the ER stress response we found that UPR inducers significantly inhibit ZIKV replication. Interestingly, our findings provide evidence that ZIKV can altered the UPR in order to escape to the host cell defense system.

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The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly

Cited by 29 publications

References 99 publications

Glucose-Regulated Protein 78 Interacts with Zika Virus Envelope Protein and Contributes to a Productive Infection

Glucose-Regulated Protein 78 Interacts with Zika Virus Envelope Protein and Contributes to a Productive Infection

Asian Zika virus isolate significantly changes the transcriptional profile and alternative RNA splicing events in a neuroblastoma cell line

Crosstalk Between Endoplasmic Reticulum Stress and The Unfolded Protein Response During ZIKA Virus Infection

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