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

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. Protein-protein interactions underlie all aspects of a viral infection. Here the authors employ a pan-viral approach for systematic identification of motif-mediated interactions between viral and human proteins and show that the information can be used to find targets for antiviral drug development.

Automated summary

Viruses hijack and deregulate cellular functions by mimicking host short linear motifs (SLiMs). In this study, a pan-viral approach is used to discover 1712 SLiM-based virus-host interactions, revealing novel host proteins hijacked by viruses and cellular pathways frequently deregulated. Furthermore, structural and biophysical analyses demonstrate that viral mimicry-based interactions have similar properties to endogenous interactions. The discovery of polyadenylate-binding protein 1 as a potential antiviral target highlights the therapeutic potential of this research in combating epidemics and pandemics.