MEK/ERK activation plays a decisive role in yellow fever virus replication: Implication as an antiviral therapeutic target

Albarnaz, Jonas D.; Oliveira, Leonardo Camilo de; Torres, Alice A.; Palhares, Rafael Melo; Casteluber, Marisa C. F.; Rodrigues, Claudiney Melquíades; Cardozo, Pablo Leal; Souza, Aryádina M.R. De; Pacca, Carolina Colombelli; Ferreira, Paulo César Peregrino; Kroon, Erna Geessien; Nogueira, Maurício Lacerda; Bonjardim, Cláudio Antônio

doi:10.1016/j.antiviral.2014.09.004

Cited by 45 publications

(35 citation statements)

References 49 publications

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“…Dengue virus serotype 2 (DENV-2) participates in liver inflammation by inducing the expression of various chemokines through activating all three MAPK pathways (52). YFV infection induces ERK1/2 activation, and treatment with U0126 reduces the level of YFV replication by 99% (38). A similar inhibitory effect of the ERK inhibitor was also observed in infections with dengue virus (DENV-2 and -3) and St. Louis encephalitis virus (SLEV) (38).…”

Section: Discussionmentioning

confidence: 61%

“…YFV infection induces ERK1/2 activation, and treatment with U0126 reduces the level of YFV replication by 99% (38). A similar inhibitory effect of the ERK inhibitor was also observed in infections with dengue virus (DENV-2 and -3) and St. Louis encephalitis virus (SLEV) (38). AMPK, an intracellular energy sensor, plays a pivotal role in cellular metabolism, particularly in lipid and glucose metabolism (53).…”

Section: Discussionmentioning

confidence: 90%

“…Viruses often hijack host cellular signaling pathways to facilitate their infection and replication. Several pathways, such as the MAPK, PKA, and AMPK pathways, have been reported to play important roles in flavivirus replication (35)(36)(37)(38)(39). To determine if these pathways are essential for ZIKV infection, HUVEC were first preincubated with either an inhibitor or an agonist of a corresponding signaling pathway and then infected with ZIKV in the presence of the chemical compound.…”

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confidence: 99%

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Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

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Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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“…In turn, the MEK1/2 [mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) kinase]/ERK1/2 signaling pathway prevents the LKB1-AMPK signaling [61], thus the stimulation of the MEK/ERK pathway in DENV infected cells could explain the depletion of AMPK phosphorylation. Several authors demonstrated that DENV [62] and others flaviviruses including Hepatitis C Virus (HCV) [63], West Nile fever virus (WNV) [64], Japanese encephalitis virus (JEV) [65] and yellow fever virus (YFV) [66] cause the turn on of the MEK/ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Soto-Acosta¹,

et al. 2017

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Dengue is the most common mosquito-borne viral disease in humans. Changes of lipid-related metabolites in endoplasmic reticulum of dengue virus (DENV) infected cells have been associated with replicative complexes formation. Previously, we reported that DENV infection inhibits HMGCR phosphorylation generating a cholesterol-enriched cellular environment in order to favor viral replication. In this work, using enzymatic assays, ELISA, and WB we found a significant higher activity of HMGCR in DENV infected cells, associated with the inactivation of AMPK. AMPK activation by metformin declined the HMGCR activity suggesting that AMPK inactivation mediates the enhanced activity of HMGCR. A reduction on AMPK phosphorylation activity was observed in DENV infected cells at 12 and 24 hpi. HMGCR and cholesterol co-localized with viral proteins NS3, NS4A and E, suggesting a role for HMGCR and AMPK activity in the formation of DENV replicative complexes. Furthermore, metformin and lovastatin (HMGCR inhibitor) altered this co-localization as well as replicative complexes formation supporting that active HMGCR is required for replicative complexes formation. In agreement, metformin prompted a significant dose-dependent antiviral effect in DENV infected cells, while compound C (AMPK inhibitor) augmented the viral genome copies and the percentage of infected cells. The PP2A activity, the main modulating phosphatase of HMGCR, was not affected by DENV infection. These data demonstrate that the elevated activity of HMGCR observed in DENV infected cells is mediated through AMPK inhibition and not by increase in PP2A activity. Interestingly, the inhibition of this phosphatase showed an antiviral effect in an HMGCR-independent manner. These results suggest that DENV infection increases HMGCR activity through AMPK inactivation leading to higher cholesterol levels in endoplasmic reticulum necessary for replicative complexes formation. This work provides new information about the mechanisms involved in host lipid metabolism during DENV replicative cycle and identifies new potential antiviral targets for DENV replication.

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“…Cellular signalling cascades are key to these regulatory events because they can be rapidly activated or deactivated and not only are vital in controlling important cellular processes but also modulate viral propagation. Flaviviruses, including yellow fever virus, Saint Louis encephalitis virus, and dengue virus, as well depend on Raf/MEK/ERK-mediated signalling for efficient replication (Albarnaz et al, 2014). Several cascades have been described to be involved in viral replication, such as the PI3K/Akt cascade, MAPK cascade, PKC/PKR cascade, and NF-κB signalling module (reviewed in Gaur, Munjal, & Lal, 2011;reviewed in Diehl & Schaal, 2013 Pleschka et al, 2001;Zheng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Late activation of theRaf/MEK/ERKpathway is required for translocation of the respiratory syncytial virusFprotein to the plasma membrane and efficient viral replication

Preugschas

Hrincius

Mewis

et al. 2018

Cellular Microbiology

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Activation of the Raf/MEK/ERK cascade is required for efficient propagation of several RNA and DNA viruses, including human respiratory syncytial virus (RSV). In RSV infection, activation of the Raf/MEK/ERK cascade is biphasic. An early induction within minutes after infection is associated with viral attachment. Subsequently, a second activation occurs with, so far, unknown function in the viral life cycle. In this study, we aimed to characterise the role of Raf/MEK/ERK-mediated signalling during ongoing RSV infection. Our data show that inhibition of the kinase MEK after the virus has been internalised results in a reduction of viral titers. Further functional investigations revealed that the late-stage activation of ERK is required for a specific step in RSV replication, namely, the secretory transport of the RSV fusion protein F. Thus, MEK inhibition resulted in impaired surface accumulation of the F protein. F protein surface expression is essential for efficient replication as it is involved in viral filament formation, cell fusion, and viral transmission. In summary, we provide detailed insights of how host cell signalling interferes with RSV replication and identified the Raf/MEK/ERK kinase cascade as potential target for novel anti-RSV strategies.

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MEK/ERK activation plays a decisive role in yellow fever virus replication: Implication as an antiviral therapeutic target

Cited by 45 publications

References 49 publications

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target

Late activation of theRaf/MEK/ERKpathway is required for translocation of the respiratory syncytial virusFprotein to the plasma membrane and efficient viral replication

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