EGR1 upregulation following Venezuelan equine encephalitis virus infection is regulated by ERK and PERK pathways contributing to cell death

Dahal, Bibha; Lin, Shih‐Chao; Carey, Brian D.; Jacobs, Jonathan L.; Dinman, Jonathan D.; Hoek, Monique L. van; Adams, André A.

doi:10.1016/j.virol.2019.10.016

Cited by 17 publications

(18 citation statements)

References 41 publications

(54 reference statements)

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“…Unknown Whether Alphaviruses Activate PI3K-AKT to Promote Cell Survival Many AKT substrates play a role in promoting cell survival and proliferation, but there are currently no studies addressing the effects of AKT on cell death in alphavirus infection. The New World alphavirus Venezuelan equine encephalitis virus stimulates early growth factor response genes in infected astrocytes, but this was shown not to be dependent on MAPK or PI3K signaling [54]. Rubella virus (RV) which also belongs to the Togaviridae family, induces caspase-dependent apoptosis, leading to a cytopathic effect, but delays and reduces this process through PI3K-AKT activation [55].…”

Section: Promotion Of Cell Survivalmentioning

confidence: 99%

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Huizen

McInerney

2020

Cells

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Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, there are no vaccines or antiviral therapies for any alphavirus. Several Old World alphaviruses, including Semliki Forest virus, Ross River virus and chikungunya virus, activate or hyperactivate the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in vertebrate cells, potentially influencing many cellular processes, including survival, proliferation, metabolism and autophagy. Inhibition of PI3K or AKT inhibits replication of several alphaviruses either in vitro or in vivo, indicating the importance for viral replication. In this review, we discuss what is known about the mechanism(s) of activation of the pathway during infection and describe those effects of PI3K-AKT activation which could be of advantage to the alphaviruses. Such knowledge may be useful for the identification and development of therapies.Cells 2020, 9, 970 2 of 12 complex mTORC1. AKT signalling leads to the activation of mTORC1, which promotes cell growth by inducing lipid biogenesis through activation of the transcription factors SREBP1 and PPARγ and by promoting protein synthesis by activating the S6 kinase (S6K) and by inactivating the translational inhibitor 4E-BP1. mTORC1 also inhibits autophagy by blocking ULK1 [6]. The serine/threonine kinase glycogen synthase kinase 3 (GSK3) is another multifunctional target of AKT. Through phosphorylation, active GSK3 inhibits most of its substrates. Upon phosphorylation by AKT, GSK3 itself is inhibited and thereby the downstream targets are positively regulated. These targets include the prosurvival BCL-2 family member MCL-1 and the transcription factor c-Myc, which is required for expression of many genes involved in proliferation. Other GSK3-targets, such as glycogen synthase, are involved in (regulation of) cellular metabolism [7]. The third multifunctional target of AKT are the forkhead box O (FoxO) transcription factors. Phosphorylation of FoxO transcription factors by AKT leads to acute translocation out of the nucleus. Thus, AKT signalling suppresses the expression of FoxO targets. These include targets involved in the induction of apoptosis, cell-cycle arrest, catabolic metabolism and growth inhibition. Thus, PI3K-AKT signalling via these multifunctional targets promotes cell survival, growth and proliferation and steers cellular metabolism towards anabolism.

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Section: Promotion Of Cell Survivalmentioning

confidence: 99%

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Huizen

McInerney

2020

Cells

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“…After prolonged periods of ER stress, apoptosis is triggered via the PERK pathway [ 20 , 21 ]. VEEV and SINV has been found to induce the activation of the PERK arm of the UPR pathway [ 22 , 23 ]. On the other hand, CHIKV inhibits activation of the PERK pathway by suppressing the phosphorylation of eukaryotic translation initiation factor alpha (eIF2α) [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections

et al. 2021

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Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking.

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“…Endoplasmic reticulum stress response has been described in flavivirus-infected cells, but little is known about alphaviruses. However, SFV envelope glycoproteins, but not capsid, seem able to induce and accelerate apoptotic cell death [104], while VEEV glycoproteins induce UPR and apoptosis in primary astrocytes [105,106].…”

Section: Apoptotic Pathways In Alphavirus-infected Cellsmentioning

confidence: 99%

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Cappuccio

Maisse

2020

Cells

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Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes.

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EGR1 upregulation following Venezuelan equine encephalitis virus infection is regulated by ERK and PERK pathways contributing to cell death

Cited by 17 publications

References 41 publications

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

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