An atlas of protein-protein interactions across mouse tissues

Cellular processes arise from the dynamic organization of proteins in networks of physical interactions. Mapping the interactome has therefore been a central objective of high-throughput biology. However, the dynamics of protein interactions across physiological contexts remain poorly understood. Here, we develop a quantitative proteomic approach combining protein correlation profiling with stable isotope labeling of mammals (PCP-SILAM) to map the interactomes of seven mouse tissues. The resulting maps provide a proteome-scale survey of interactome rewiring across mammalian tissues, revealing more than 125,000 unique interactions at a quality comparable to the highest-quality human screens. We identify systematic suppression of cross-talk between the evolutionarily ancient housekeeping interactome and younger, tissue-specific modules. Rewired proteins are tightly regulated by multiple cellular mechanisms and are implicated in disease. Our study opens up new avenues to uncover regulatory mechanisms that shape in vivo interactome responses to physiological and pathophysiological stimuli in mammalian systems. [Display omitted] •PCP-SILAM enables in vivo interactome mapping of seven mouse tissues•A high-quality map more than doubles the size of the known mouse interactome•Rewiring of protein interactions across tissues is tightly regulated•Proteins implicated in tissue-specific diseases form tissue-specific subnetworks Systematic in vivo mapping of protein-protein interactions in seven mouse tissues provides insights into tissue-specific interaction rewiring and its role in disease.