Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A

Cencic, Regina

doi:10.1080/21690731.2015.1137381

Cited by 52 publications

(62 citation statements)

References 114 publications

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“…It induces PKR activation and subsequent eIF2␣ phosphorylation. In contrast, hippuristanol stimulates SG formation through an eIF2␣-independent mechanism by interfering with the RNA-binding activity of the translation initiation factor eIF4A (40,41).…”

Section: Resultsmentioning

confidence: 99%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

114

132

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Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2␣ and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication.IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication.

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Section: Resultsmentioning

confidence: 99%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

114

132

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“…There are some compounds that have the characteristic of inhibiting eIF4A: silvestrol [59], hippuristanol [60], elisabatin and allolaurintenol [61], rocaglamide [62], and pateamine A and some of its derivatives [30]. These compounds are emerging as a new antiviral therapeutic strategy whose mechanism of action is the inhibition of eIF4A.…”

Section: The Eif4a Inhibitorsmentioning

confidence: 99%

Eukaryotic initiation factor 4A (eIF4A) during viral infections

2019

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The helicase eIF4A is part of the cellular eIF4F translation initiation complex. The main functions of eIF4A are to remove secondary complex structures within the 5′-untranslated region and to displace proteins attached to mRNA. As intracellular parasites, viruses regulate the processes involved in protein synthesis, and different mechanisms related to controlling translation factors, such as eIF4A, have been found. The inhibitors of this factor are currently known; these substances could be used in the near future as part of antiviral pharmacological therapies in instances of replication cycles in which eIF4A is required. In this review, the particularities of how some viruses make use of this initiation factor to synthesize their proteins are discussed.

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“…The majority of eIF4A exists as free form while only a small fraction is present as the eIF4F subunit [2]. The higher eIF4A abundance, relative to eIF4F, has led to models invoking recycling of eIF4A through the eIF4F complex during translation initiation [3]. 43S complex then scans the 5′ untranslated region of the mRNA until the initiation AUG codon in an optimum context.…”

Section: Overview Of Initiation Of Protein Synthesismentioning

confidence: 99%

Serine-threonine protein phosphatases: Lost in translation

Kolupaeva¹

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein synthesis is one of the most complex and energy-consuming processes in eukaryotic cells and therefore is tightly regulated. One of the main mechanisms of translational control is post-translational modifications of the components of translational apparatus. Phosphorylation status of translation factors depends on the balanced action of kinases and phosphatases. While many kinase-dependent events are well defined, phosphatases that counteract phosphorylation are rarely determined. This mini-review focuses on the regulation of activity of translational initiation factors by Serine/Threonine phosphatases.

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Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A

Cited by 52 publications

References 114 publications

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Eukaryotic initiation factor 4A (eIF4A) during viral infections

Serine-threonine protein phosphatases: Lost in translation

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