Dynamic rewiring of the human interactome by interferon signaling

Craig H. Kerr, Michael A. Skinnider, Daniel D.T. Andrews, Angel M. Madero, Queenie W.T. Chan, R. Greg Stacey, Nikolay Stoynov, Eric Jan, Leonard J. Foster

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background: The 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. Comprehensive catalogs of IFN-stimulated genes have been established across species and cell types by transcriptomic and biochemical approaches, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to describe the effects of IFN signaling on the human proteome, and apply protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network. Results: We identify > 26,000 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 IFN-stimulated gene protein synthesis. Conclusions: Our map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing IFN-stimulated genes in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease.

Original languageEnglish (US)
Article number140
JournalGenome biology
Volume21
Issue number1
DOIs
StatePublished - Jun 15 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Cell Biology

Keywords

  • Innate immunity
  • Interactome
  • Interferon
  • Interferon-stimulated gene
  • Protein complexes
  • Protein correlation profiling
  • Proteomics

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