Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication

Lundberg, Lindsay; Pinkham, Chelsea; Baer, Alan N.; Amaya, Moushimi; Narayanan, Aarthi; Wagstaff, Kylie M.; Jans, David A.; Kehn-Hall, Kylene

doi:10.1016/j.antiviral.2013.10.004

Cited by 170 publications

(175 citation statements)

References 33 publications

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“…U87MG cells are readily infected by VEEV and display robust viral replication kinetics. [6][7][8][28][29][30] U87MG cells were infected with the TC-83 strain of VEEV at increasing multiplicities of infection (MOIs). Changes in mitochondrial membrane potential were quantified by labeling active mitochondria with TMRE reagent (TetraMethyl Rhodamine, Ethyl ester).…”

Section: Veev Infection Results In Loss Of Mitochondrial Membrane Potmentioning

confidence: 99%

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell.

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Section: Veev Infection Results In Loss Of Mitochondrial Membrane Potmentioning

confidence: 99%

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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“…Mouse embryonic fibroblasts (MEFs), U87MG, and Vero cells were cultured in Dulbecco's modified Eagle's media (DMEM), supplemented and maintained as described in Lundberg et al (2013). MEFs deficient in Ago2 (Ago2 À/À MEFs) were obtained through Dr. G. Hannon of Cold Spring Harbor (Liu et al, 2004).…”

Section: Cell Culturementioning

confidence: 99%

“…Cells were infected with VEEV-GFP, at an MOI of 1.0 and collected at 24 h post infection. All above samples were processed as described in Lundberg et al (2013). Cells were analyzed on an Accuri C6 Flow Cytometer using a CFlow Plus analysis platform to detect GFP expression.…”

Section: Flow Cytometrymentioning

confidence: 99%

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Small molecule inhibitors of Ago2 decrease Venezuelan equine encephalitis virus replication

et al. 2014

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“…that Ivermectin possesses potent antiviral activity by inhibiting replication of human immunodeficiency virus (HIV) and dengue virus due to its effect on importins (Wagstaff et al, 2012;Tay et al, 2013;Fraser et al, 2014). Furthermore, it is able to alter capsid protein distribution in mammalian cells resulting in a reduced replication of Venezuelan Equine Encephalitis virus (Lundberg et al, 2013). Recently, Lokich et al found that treatment with Ivermectin sensitises human epididymis protein 4 (HE4)-overexpressing ovarian cancer cells to the chemotherapeutics fulvestrant and tamoxifen.…”

Section: Introductionmentioning

confidence: 97%

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

Kosyna

Nagel²,

Kluxen

et al. 2015

Biological Chemistry

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Hypoxia-inducible transcription factors (HIFs) regulate hundreds of genes involved in cellular adaptation to reduced oxygen availability. HIFs consist of an O2-labile α-subunit (primarily HIF-1α and HIF-2α) and a constitutive HIF-1β subunit. In normoxia the HIF-α subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1-3, resulting in recognition by von Hippel-Lindau protein, ubiquitination and proteasomal degradation. In contrast, reduced oxygen availability inhibits PHD activity resulting in HIF-1α stabilisation and nuclear accumulation. Nuclear import of HIF-1α mainly depends on classical nuclear localisation signals (NLS) and involves importin α/β heterodimers. Recently, a specific inhibitor of nuclear import has been identified that inhibits importin α/β-dependent import with no effects on a range of other nuclear transport pathways involving members of the importin protein family. In this study we evaluated the physiological activity of this importin α/β-inhibitor (Ivermectin) in the hypoxia response pathway. Treatment with Ivermectin decreases binding activity of HIF-1α to the importin α/β-heterodimer. Moreover, HIF-1α nuclear localisation, nuclear HIF-1α protein levels, HIF-target gene expression, as well as HIF-transcriptional activity are reduced upon Ivermectin treatment. For the first time, we demonstrate the effect of specific importin α/β-inhibition on the hypoxic response on the molecular level.

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Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication

Cited by 170 publications

References 33 publications

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

Small molecule inhibitors of Ago2 decrease Venezuelan equine encephalitis virus replication

The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways

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