Global Reprogramming of the Cellular Translational Landscape Facilitates Cytomegalovirus Replication

McKinney, Caleb; Zavadil, Jiří; Bianco, Christopher; Shiflett, Lora A.; Brown, Stuart M.; Mohr, Ian

doi:10.1016/j.celrep.2013.11.045

Cited by 41 publications

(46 citation statements)

References 37 publications

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“…This mechanism might also explain why convallatoxin has been a successful cancer treatment in vitro, preferentially killing cancer cells versus healthy cells, and appears to have a mechanism distinct from those of all other classical cancer drugs (36). In fact, the gene expression changes in the cell are similar in CMV infection and cancer (37). Convallatoxin can be safely consumed orally by rats at a daily dosage of roughly 0.76 mg/kg of body weight (38), which would translate to a little over 50 mg/day orally in a 70-kg person.…”

Section: Discussionmentioning

confidence: 99%

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Cohen

Williams

Opperman

et al. 2016

J Virol

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Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases the morbidity and mortality of immunocompromised individuals. The current FDA-approved treatments for CMV infection are intended to be virus specific, yet they have significant adverse side effects, including nephrotoxicity and hematological toxicity. Thus, there is a medical need for safer and more effective CMV therapeutics. Using a high-content screen, we identified the cardiac glycoside convallatoxin as an effective compound that inhibits CMV infection. Using a panel of cardiac glycoside variants, we assessed the structural elements critical for anti-CMV activity by both experimental and in silico methods. Analysis of the antiviral effects, toxicities, and pharmacodynamics of different variants of cardiac glycosides identified the mechanism of inhibition as reduction of methionine import, leading to decreased immediate-early gene translation without significant toxicity. Also, convallatoxin was found to dramatically reduce the proliferation of clinical CMV strains, implying that its mechanism of action is an effective strategy to block CMV dissemination. Our study has uncovered the mechanism and structural elements of convallatoxin, which are important for effectively inhibiting CMV infection by targeting the expression of immediate-early genes. IMPORTANCECytomegalovirus is a highly prevalent virus capable of causing severe disease in certain populations. The current FDA-approved therapeutics all target the same stage of the viral life cycle and induce toxicity and viral resistance. We identified convallatoxin, a novel cell-targeting antiviral that inhibits CMV infection by decreasing the synthesis of viral proteins. At doses low enough for cells to tolerate, convallatoxin was able to inhibit primary isolates of CMV, including those resistant to the anti-CMV drug ganciclovir. In addition to identifying convallatoxin as a novel antiviral, limiting mRNA translation has a dramatic impact on CMV infection and proliferation. C ytomegalovirus (CMV) is an extremely large betaherpesvirus with over 230,000 bp and over 200 open reading frames. While the majority of CMV infections in immunocompetent hosts are asymptomatic (1), the phenomenon of latency allows the virus to establish a permanent and persistent infection. CMV is highly seroprevalent in the human population (Ͼ60%), with broad cell tropism, and can be transmitted through bodily fluids and organ transplantation and transplacentally from mother to fetus (2). Reactivation of latent CMV can cause disease in any population but is a particular source of morbidity and mortality for immunocompromised patients (3). It is estimated that treatment of CMV costs the United States $4.4 billion every year (4), and congenital CMV infections are the leading cause of permanent congenital neurological disabilities in the United States (5). The current FDA-approved therapies all target the viral DNA polymerase, and none are approved for use in pregnant women or newborns. These compounds can cause sever...

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Section: Discussionmentioning

confidence: 99%

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Cohen

Williams

Opperman

et al. 2016

J Virol

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“…In support of this model, another cap-binding protein, eIF4E3, has been suggested to regulate translation under other settings (Landon et al, 2014). Thus, it is likely that cells have evolved multiple alternative translation initiation machineries that allow them to activate stimulus-specific translation efficiency programs (Andreev et al, 2015; Baudin-Baillieu et al, 2014; Kronja et al, 2014; Lu et al, 2009; McKinney et al, 2014; Ventoso et al, 2012; Young et al, 2008). These alternative machineries would reprogram global mRNA translation efficiencies in order to generate distinct, adaptive translatomes/proteomes.…”

Section: Discussionmentioning

confidence: 99%

Systemic Reprogramming of Translation Efficiencies on Oxygen Stimulus

et al. 2016

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Summary Protein concentrations evolve under greater evolutionary constraint than mRNA levels. Translation efficiency of mRNA represents the chief determinant of basal protein concentrations. This raises a fundamental question of how mRNA and protein levels are coordinated in dynamic systems responding to physiological stimuli. This report examines the contributions of mRNA abundance and translation efficiency to protein output in cells responding to oxygen stimulus. We show that changes in translation efficiencies, not mRNA levels, represent the major mechanism governing cellular responses to [O2] perturbations. Two distinct cap-dependent protein synthesis machineries select mRNAs for translation: the normoxic eIF4F and the hypoxic eIF4FH. O2-dependent remodeling of translation efficiencies enables cells to produce adaptive translatomes from preexisting mRNA pools. Differences in mRNA expression observed under different [O2] are likely neutral, as they are during evolution. We propose that mRNAs contain translation efficiency determinants for their triage by the translation apparatus on [O2] stimulus.

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“…eIF6 protein levels were stimulated under HCMV infection and eIF6 depletion stimulated virus replication approximately 20-fold. Interestingly, as eIF6-depletion enhanced viral replication, its induction by infection could therefore represent a host defense [37]. Indeed, preliminary data suggest that the physiological levels of eIF6 are evolutionarily conserved to ensure immune system's defense.…”

Section: Eif6 Antiassociation Activity In Translation In Normal Tissuesmentioning

confidence: 96%

eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression

Brina

Miluzio

Ricciardi

et al. 2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Global Reprogramming of the Cellular Translational Landscape Facilitates Cytomegalovirus Replication

Cited by 41 publications

References 37 publications

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication

Systemic Reprogramming of Translation Efficiencies on Oxygen Stimulus

eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression

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