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. 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFNstimulated genes
We develop statistical methods for differential network analysis to characterize interactome rewiring at the functional level, leading us to identify alterations in ribosome composition induced by interferon signaling that selectively downregulate IFN-stimulated genes (ISGs) synthesis in order to fine-tune the IFN response
In view of the multiple biological mechanisms that exist to decouple protein abundance from mRNA expression [18], we first sought to establish the proteome-wide response to IFN-β stimulation
Summary
The type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFNstimulated genes. IFN stimulation induces a complex response that is not limited to a simple antiviral program, but instead activates a number of additional signaling pathways such as the MAPK cascade and the mTOR-AKTS6K axis, which contribute to ISG induction or the antiviral response more broadly [3]. This cascade results in substantial remodeling of mRNA processing, posttranslational modifications, metabolism, cellular trafficking, chromatin organization, and the cytoskeleton, among other processes [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
