Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

Sage, Valerie Le; Cinti, Alessandro; Amorim, Raquel Beltrão; Mouland, Andrew J.

doi:10.3390/v8060152

Cited by 99 publications

(103 citation statements)

References 152 publications

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“…Viral infection is a significant stress which can activate, reduce or even suppress the mTOR signaling pathway. Furthermore, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make a hospitable environment for replication in host cells [54]. In our study, upon PEDV infection, most of the genes in the mTOR signaling pathway underwent down-regulation compared with the mock group.…”

Section: Discussionmentioning

confidence: 60%

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

Zhang

Liu

et al. 2018

Microbial Pathogenesis

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PEDV remains one of the most important swine diseases that infects pigs of all ages. It causes devastating viral enteric disease in piglets with a high mortality rate, leading to significant threats and huge economic loss to the pork industry. In this study, a transcriptomic shotgun sequencing (RNA-Seq) procedure was used to study gene responses against PEDV infection. Genome-wide analysis of differentially expressed genes (DEGs) was performed in Vero E6 cells post-PEDV infection. mTOR signaling pathway activator-MHY1485, and inhibitor-PP242 were used to study the antiviral function. Results revealed that the IRF3 was significantly up-regulated post-PEDV infection. Although most of the IFN-regulatory and -related genes evaluated in this study were either down-regulated or remained unchanged, IL11 behaved significantly up-regulated, with the peak at 16 hpi. Nearly 90% of PEDV infections were suppressed in the PP242 pretreated cells whereas the reverse effect was observed in the MYH1485 pretreated cells. Results indicated that the mTOR signaling pathway played a vital role in the PEDV antiviral regulation in the Vero E6 cells. Future studies will contribute to better understand the cellular antiviral mechanism against PEDV.

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Section: Discussionmentioning

confidence: 60%

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

Zhang

Liu

et al. 2018

Microbial Pathogenesis

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“…While Ribavirin has activity against SARS in vitro 81 , it has low tolerability, something that might be addressed by the more selective Merimepodib, which is in phase II clinical trials 82 . (c) The mammalian target of Rapamycin (mTOR) pathway is a master regulator of cell proliferation and autophagy, which viruses including Influenza A are known to modulate 83,84 . Several proteins that interact with SARS-CoV-2 baits, including components of the Respiratory complex 1 by Nsp7, Nsp12, and Orf9c, the leucine importer B(0)AT2 (SLC6A15) 85,86 by Nsp6 and LARP1) by N (not shown).…”

Section: Discussionmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

431

586

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ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

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“…It is a central cellular sensor system that is responsible for the reaction and adjustment to cellular stress such as oxidative stress, nitrogen starvation, and flaviviral infections (75,76). The fine balance between autophagy and programmed cell death following viral infection is controlled in part by the TOR pathway (77).…”

Section: Discussionmentioning

confidence: 99%

Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast

Poulsen

Fenyvuesvolgyi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The Zika virus (ZIKV) causes microcephaly and the Guillain-Barré syndrome. Little is known about how ZIKV causes these conditions or which ZIKV viral protein(s) is responsible for the associated ZIKVinduced cytopathic effects, including cell hypertrophy, growth restriction, cell-cycle dysregulation, and cell death. We used fission yeast for the rapid, global functional analysis of the ZIKV genome. All 14 proteins or small peptides were produced under an inducible promoter, and we measured the intracellular localization and the specific effects on ZIKV-associated cytopathic activities of each protein. The subcellular localization of each ZIKV protein was in overall agreement with its predicted protein structure. Five structural and two nonstructural ZIKV proteins showed various levels of cytopathic effects. The expression of these ZIKV proteins restricted cell proliferation, induced hypertrophy, or triggered cellular oxidative stress leading to cell death. The expression of premembrane protein (prM) resulted in cell-cycle G1 accumulation, whereas membrane-anchored capsid (anaC), membrane protein (M), envelope protein (E), and nonstructural protein 4A (NS4A) caused cell-cycle G2/M accumulation. A mechanistic study revealed that NS4A-induced cellular hypertrophy and growth restriction were mediated specifically through the target of rapamycin (TOR) cellular stress pathway involving Tor1 and type 2A phosphatase activator Tip41. These findings should provide a reference for future research on the prevention and treatment of ZIKV diseases. T he recent Zika virus (ZIKV) outbreak was surprising in its rapidity and alarming in its association with microcephaly in newborns (1-3) and the Guillain-Barré syndrome in adults (4, 5). Currently, little is known about ZIKV pathogenicity. ZIKV infects various neuronal cells and affects brain neurogenesis by reducing cellular proliferation and inducing cell-cycle abnormalities, cell death/apoptosis, and autophagy (2, 3, 6-8). However, it is not known which viral determinant(s) cause these cytopathic effects. The objective of this study was to identify ZIKV factors responsible for the ZIKV-mediated cytopathic effects that underlie the diseases associated with ZIKV.

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Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

Cited by 99 publications

References 152 publications

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

Genome-wide analysis of differentially expressed genes and the modulation of PEDV infection in Vero E6 cells

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast

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