Structural host-virus interactome profiling of intact infected cells

Boris Bogdanow (), Lars Mühlberg, Iris Gruska, Barbara Vetter, Julia Ruta, Arne Elofsson, Lüder Wiebusch () and Fan Liu ()
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Boris Bogdanow: Research group “Structural Interactomics”, Leibniz Forschungsinstitut für Molekulare Pharmakologie
Lars Mühlberg: Research group “Structural Interactomics”, Leibniz Forschungsinstitut für Molekulare Pharmakologie
Iris Gruska: Charité - Universitätsmedizin Berlin
Barbara Vetter: Charité - Universitätsmedizin Berlin
Julia Ruta: Research group “Structural Interactomics”, Leibniz Forschungsinstitut für Molekulare Pharmakologie
Arne Elofsson: Stockholm Bioinformatics Center, Stockholm University
Lüder Wiebusch: Charité - Universitätsmedizin Berlin
Fan Liu: Research group “Structural Interactomics”, Leibniz Forschungsinstitut für Molekulare Pharmakologie

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Virus-host protein-protein interactions (PPIs) are fundamental to viral infections, yet high-resolution identification of their structural and molecular determinants within the native context of intact infected cells has remained an unsolved challenge. Here, we provide detailed insights into the structural interactome of herpes simplex virus 1-infected human cells by combining in-cell cross-linking mass spectrometry with the selective enrichment of newly synthesized viral proteins. In productively infected cells, we obtain 739 PPIs based on 6,194 cross-links found across intracellular compartments and at the intact host endomembrane system. These structural host-virus interactome profiling (SHVIP) data resolve PPIs to the protein domain level and augment AlphaFold-based structural modeling, facilitating detailed predictions of PPI sites within structured and intrinsically disordered regions. Importantly, SHVIP captures parts of the virus-host PPI space that are elusive to traditional interaction proteomics approaches. Validation by molecular genetics confirms that these new SHVIP identifications are genuine virus-host PPIs occurring in the complex environment of intact infected cells.

Date: 2025
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DOI: 10.1038/s41467-025-61618-z

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