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Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection.

  • Author(s): Heaton, Nicholas S;
  • Moshkina, Natasha;
  • Fenouil, Romain;
  • Gardner, Thomas J;
  • Aguirre, Sebastian;
  • Shah, Priya S;
  • Zhao, Nan;
  • Manganaro, Lara;
  • Hultquist, Judd F;
  • Noel, Justine;
  • Sachs, David;
  • Hamilton, Jennifer;
  • Leon, Paul E;
  • Chawdury, Amit;
  • Tripathi, Shashank;
  • Melegari, Camilla;
  • Campisi, Laura;
  • Hai, Rong;
  • Metreveli, Giorgi;
  • Gamarnik, Andrea V;
  • García-Sastre, Adolfo;
  • Greenbaum, Benjamin;
  • Simon, Viviana;
  • Fernandez-Sesma, Ana;
  • Krogan, Nevan J;
  • Mulder, Lubbertus CF;
  • van Bakel, Harm;
  • Tortorella, Domenico;
  • Taunton, Jack;
  • Palese, Peter;
  • Marazzi, Ivan
  • et al.
Abstract

Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling and genetic and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication, we have identified targetable host factors for broad-spectrum antiviral therapies.

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