Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Roby, Justin A; Esser-Nobis, Katharina; Dewey-Verstelle, Elyse C.; Fairgrieve, Marian R.; Schwerk, Johannes; Lu, Amy Y.; Soveg, Frank; Hemann, Emily A.; Hatfield, Lauren D.; Keller, Brian C.; Shapiro, Alexander; Forero, Adriana; Stencel-Baerenwald, Jennifer E.; Savan, Ram; Gale, Michael

doi:10.3390/cells9040899

Cited by 31 publications

(34 citation statements)

References 50 publications

(73 reference statements)

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“…S1). However, we note that the dynamics of X are not necessarily comparable to the dynamics of soluble IFNα or other cytokines, and instead X should be considered as a measure of the effective cytokine concentration rather than the measurable cytokine concentration since ZIKV can interfere with cytokine signaling, including through the JAK/STAT pathway [ 23 , 24 , 43 , 44 ].…”

Section: Resultsmentioning

confidence: 99%

Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference

et al. 2021

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Experimental Zika virus infection in non-human primates results in acute viral load dynamics that can be well-described by mathematical models. The inoculum dose that would be received in a natural infection setting is likely lower than the experimental infections and how this difference affects the viral dynamics and immune response is unclear. Here we study a dataset of experimental infection of non-human primates with a range of doses of Zika virus. We develop new models of infection incorporating both an innate immune response and viral interference with that response. We find that such a model explains the data better than models with no interaction between virus and the immune response. We also find that larger inoculum doses lead to faster dynamics of infection, but approximately the same total amount of viral production.

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Section: Resultsmentioning

confidence: 99%

Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference

et al. 2021

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“…Thus, the interaction of NS5 with cyclophilins and the corresponding inhibition by cyclosporins [ 43 ], Hsp70 [ 44 ], and with a great number of proteins related to the regulation of the immune system has been described [ 45 ]. In fact, most flavivirus NS5 interactions described so far are with proteins related to the interferon response [ 46 ], such as Hsp90 and JAK/STAT, among others [ 47 , 48 , 49 , 50 ]. It seems that the nuclear location of NS5 is not relevant to this type of modulation of the immune response [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

et al. 2021

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Usutu virus (USUV) is a flavivirus that mainly infects wild birds through the bite of Culex mosquitoes. Recent outbreaks have been associated with an increased number of cases in humans. Despite being a growing source of public health concerns, there is yet insufficient data on the virus or host cell targets for infection control. In this work we have investigated whether the cellular kinase Akt and USUV polymerase NS5 interact and co-localize in a cell. To this aim, we performed co-immunoprecipitation (Co-IP) assays, followed by confocal microscopy analyses. We further tested whether NS5 is a phosphorylation substrate of Akt in vitro. Finally, to examine its role in viral replication, we chemically silenced Akt with three inhibitors (MK-2206, honokiol and ipatasertib). We found that both proteins are localized (confocal) and pulled down (Co-IP) together when expressed in different cell lines, supporting the fact that they are interacting partners. This possibility was further sustained by data showing that NS5 is phosphorylated by Akt. Treatment of USUV-infected cells with Akt-specific inhibitors led to decreases in virus titers (>10-fold). Our results suggest an important role for Akt in virus replication and stimulate further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral target.

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“…ZIKV antagonizes IFNAR signaling as viral replication is blocked only moderately if type I IFN is applied with or after ZIKV infection [ 19 ]. NS5, the RNA-dependent RNA polymerase that replicates the viral genome, is a potent viral antagonist of IFNAR signaling [ 6 , 13 , 20 ]. NS5 proteins from African and French Polynesian isolates were reported to interact with and target STAT2 for degradation [ 6 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

Schilling

Bridgeman

Gray

et al. 2020

Cells

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The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital Zika syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system is crucial for effective control of the virus. Using CRISPR/Cas9-mediated knockouts in A549 cells, we investigated the individual contributions of the RIG-I-like receptors MDA5 and RIG-I to ZIKV sensing and control of this virus by using a Brazilian ZIKV strain. We show that RIG-I is the main sensor for ZIKV in A549 cells. Surprisingly, we observed that loss of RIG-I and consecutive type I interferon (IFN) production led to virus-induced apoptosis. ZIKV non-structural protein NS5 was reported to interfere with type I IFN receptor signaling. Additionally, we show that ZIKV NS5 inhibits type I IFN induction. Overall, our study highlights the importance of RIG-I-dependent ZIKV sensing for the prevention of virus-induced cell death and shows that NS5 inhibits the production of type I IFN.

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Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Cited by 31 publications

References 50 publications

Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference

Zika virus dynamics: Effects of inoculum dose, the innate immune response and viral interference

Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

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