Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
Mihalic, F.; Simonetti, L.; Giudice, G.; Rubin Sander, M.; Lindqvist, R.; Peters, M. B. A.; Benz, C.; Kassa, E.; Badgujar, D.; Inturi, R.; Ali, M.; Krystkowiak, I.; Sayadi, A.; Andersson, E.; Aronsson, H.; Soderberg, O.; Dobritzsch, D.; Petsalaki, E.; Overby, A. K.; Jemth, P.; Davey, N. E.; Ivarsson, Y.
Show 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 1,712 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.
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