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PloS one2015; 10(4); e0124792; doi: 10.1371/journal.pone.0124792

The ubiquitin proteasome system plays a role in venezuelan equine encephalitis virus infection.

Abstract: Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA-approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections.
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Publication Date: 2015-04-30 PubMed ID: 25927990PubMed Central: PMC4415917DOI: 10.1371/journal.pone.0124792Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research demonstrates that the Ubiquitin Proteasome System (UPS), a protein degradation mechanism, plays a significant role in Venezuelan equine encephalitis virus (VEEV) infection and that Bortezomib, a proteasome inhibitor, can effectively suppress this virus, offering a potential therapeutic avenue for treating VEEV infections.

Role of the Ubiquitin Proteasome System (UPS) in Viral Infections

  • The researchers hypothesize that a functional UPS is necessary for efficient VEEV proliferation. This hypothesis is based on prior observations where many viruses are seen to use or modify the UPS to bolster their multiplication and maintain a persistent infection.

VEEV and the Potential of Bortezomib for Treatment

  • VEEV, an important biodefense pathogen carried by mosquitoes, is currently without a vaccine or specific treatments. This makes the identification of new therapeutic targets crucial.
  • The researchers found that at non-toxic concentrations, Bortezomib, a Food and Drug Administration (FDA) approved proteasome inhibitor, became a potent inhibitor of VEEV multiplication in a human astrocytoma cell line.
  • Bortezomib was effective against both the virulent Trinidad donkey strain and the milder TC-83 strain of VEEV. This was further affirmed by observation of its effectiveness against other New World alphaviruses such as Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV).

Insights into VEEV’s Modulation of UPS

  • Through time-of-addition assays, it was observed that Bortezomib remained effective even when introduced several hours post-exposure to the virus, indicating the prolonged vulnerability of the viral process to proteasome inhibition.
  • Mass spectrometry analyses, confocal microscopy, and immunoprecipitation assays revealed that VEEV capsid protein (the protein shell of the virus) is ubiquitinated in infected cells, indicating one mechanism how the virus might be utilizing the UPS.
  • In early stages of infection, the capsid is ubiquitinated on Localization K48, which is affected by Bortezomib treatment suggesting further how Bortezomib could constrain VEEV.

Applications of the Research

  • This research provides crucial insights on how viruses might hijack the UPS for their multiplication and survival advantage.
  • Furthermore, the demonstrated efficacy of Bortezomib provides a new therapeutic target for not only VEEV but also for a broader spectrum of alphaviruses.
  • The findings will also aid in identifying host proteins that could potentially be broad therapeutic targets for alphavirus infections.

Cite This Article

APA
Amaya M, Keck F, Lindquist M, Voss K, Scavone L, Kehn-Hall K, Roberts B, Bailey C, Schmaljohn C, Narayanan A. (2015). The ubiquitin proteasome system plays a role in venezuelan equine encephalitis virus infection. PLoS One, 10(4), e0124792. https://doi.org/10.1371/journal.pone.0124792

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 10
Issue: 4
Pages: e0124792
PII: e0124792

Researcher Affiliations

Amaya, Moushimi
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Keck, Forrest
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Lindquist, Michael
  • United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
Voss, Kelsey
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Scavone, Lauren
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Kehn-Hall, Kylene
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Roberts, Brian
  • Leidos Health Life Sciences, Frederick, Maryland, United States of America.
Bailey, Charles
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.
Schmaljohn, Connie
  • United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
Narayanan, Aarthi
  • National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, United States of America.

MeSH Terms

  • Animals
  • Blotting, Western
  • Bortezomib / pharmacology
  • Cell Survival / drug effects
  • Encephalitis Virus, Venezuelan Equine / drug effects
  • Encephalitis Virus, Venezuelan Equine / pathogenicity
  • Encephalomyelitis, Venezuelan Equine / metabolism
  • Guinea Pigs
  • Immunoprecipitation
  • In Situ Hybridization, Fluorescence
  • Proteasome Endopeptidase Complex / metabolism
  • Tandem Mass Spectrometry
  • Ubiquitin / metabolism

Conflict of Interest Statement

Leidos has been affiliated with this research by providing partial financial support to the completion of this project. Leidos had no impact on the design of experiments and execution, interpretation and representation of results. This collaboration does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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