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Publications

Journal Article Ppublish

PubMed: 40381193 DOI: 10.1016/j.celrep.2025.115728

An integrated proteomics approach identifies phosphorylation sites on viral and host proteins that regulate West Nile virus infection.

Cell Rep 44(5):115728

Authors: Zachary Walter, Minghua Li, Melissa Molho, Lauren Berish, Andrew Isopi, Mary O'Mara, Mark Dittmar, Chike Nwaezeapu, Alicia Richards, Martin McCullagh, Nevan J Krogan, Sara Cherry, Jeffrey R Johnson, Holly Ramage

Affiliations

  • Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA.
  • Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
  • Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA; The J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Abstract

Upon infection, viruses alter the proteome, creating a hospitable environment for infection. Cells respond to limit viral replication, including through protein regulation by post-translational modifications. We use mass spectrometry to define proteome alterations during West Nile virus (WNV) infection. Our studies identify upregulation of HERPUD1, which restricts WNV replication through a mechanism independent of its role in endoplasmic reticulum (ER)-associated degradation (ERAD). We also identify modifications on viral proteins, including a WNV NS3 phosphorylation site that impacts viral replication. Finally, we reveal activation of two host kinases with antiviral activity. We identify phosphorylation at S108 of AMPKβ1, a non-catalytic subunit that regulates activity of the AMPK complex. We also show activation of PAK2 by phosphorylation at S141, which restricts translation of the viral genome. This work contributes to our understanding of the interplay between host and virus while providing a resource to define the changes to the proteome that regulate viral infection.

MeSH

West Nile Fever, West Nile Virus, Biological Science Disciplines, Virus Replication, Viruses, Proteomics, Immunity, Innate, Proteome, Infections, Virus Diseases

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