Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs

Filip Mihalič, Leandro Simonetti, Girolamo Giudice, Marie Rubin Sander, Richard Lindqvist, Marie Berit Akpiroro Peters, Caroline Benz, Eszter Kassa, Dilip Badgujar, Raviteja Inturi, Muhammad Ali, Izabella Krystkowiak, Ahmed Sayadi, Eva Andersson, Hanna Aronsson, Ola Söderberg, Doreen Dobritzsch, Evangelia Petsalaki, Anna K. Överby, Per Jemth (), Norman E. Davey () and Ylva Ivarsson ()
Additional contact information
Filip Mihalič: Uppsala University
Leandro Simonetti: Uppsala University
Girolamo Giudice: European Molecular Biology Laboratory-European Bioinformatics Institute
Marie Rubin Sander: Uppsala University
Richard Lindqvist: Umeå University
Marie Berit Akpiroro Peters: Umeå University
Caroline Benz: Uppsala University
Eszter Kassa: Uppsala University
Dilip Badgujar: Uppsala University
Raviteja Inturi: Uppsala University
Muhammad Ali: Uppsala University
Izabella Krystkowiak: The Institute of Cancer Research
Ahmed Sayadi: Uppsala University
Eva Andersson: Uppsala University
Hanna Aronsson: Uppsala University
Ola Söderberg: Uppsala University
Doreen Dobritzsch: Uppsala University
Evangelia Petsalaki: European Molecular Biology Laboratory-European Bioinformatics Institute
Anna K. Överby: Umeå University
Per Jemth: Uppsala University
Norman E. Davey: The Institute of Cancer Research
Ylva Ivarsson: Uppsala University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38015-5

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DOI: 10.1038/s41467-023-38015-5

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