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bioRxiv · 10.1101/766808

Dynamic rewiring of the human interactome by interferon signalling

Kerr, C. H.·Skinnider, M. A.·Madero, A. M.·Andrews, D. D.·Stacey, R. G.·Chan, Q. W.·Stoynov, N.·Jan, E.·Foster, L. J.
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Abstract

BackgroundThe type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to delineate the effects of IFN signalling on the human proteome, culminating in the use of protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network.\n\nResultsWe identified >27,000 protein interactions in IFN-stimulated and unstimulated cells, many of which involve proteins associated with human disease and are observed exclusively within the IFN-stimulated network. Differential network analysis reveals interaction rewiring across a surprisingly broad spectrum of cellular pathways in the antiviral response. We identify IFN-dependent protein-protein interactions mediating novel regulatory mechanisms at the transcriptional and translational levels, with one such interaction modulating the transcriptional activity of STAT1. Moreover, we reveal IFN-dependent changes in ribosomal composition that act to buffer ISG protein synthesis.\n\nConclusionsOur map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing ISGs in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease.

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Kerr, C. H., Skinnider, M. A., Madero, A. M., Andrews, D. D., Stacey, R. G., Chan, Q. W., Stoynov, N., Jan, E., Foster, L. J.. 2019-09-12. Dynamic rewiring of the human interactome by interferon signalling. https://doi.org/10.1101/766808

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