Skinnider Michael A, Scott Nichollas E, Prudova Anna, Kerr Craig H, Stoynov Nikolay, Stacey R Greg, Chan Queenie W T, Rattray David, Gsponer Jörg, Foster Leonard J
Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Peter Doherty Institute, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3000, Australia.
Cell. 2021 Jul 22;184(15):4073-4089.e17. doi: 10.1016/j.cell.2021.06.003. Epub 2021 Jul 1.
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.
细胞过程源于蛋白质在物理相互作用网络中的动态组织。因此，绘制相互作用组图谱一直是高通量生物学的核心目标。然而，蛋白质相互作用在不同生理环境下的动态变化仍知之甚少。在此，我们开发了一种定量蛋白质组学方法，将蛋白质相关性分析与哺乳动物稳定同位素标记（PCP-SILAM）相结合，以绘制七种小鼠组织的相互作用组图谱。所得图谱提供了跨哺乳动物组织的相互作用组重连的蛋白质组规模调查，揭示了超过125,000种独特的相互作用，其质量与最高质量的人类筛选相当。我们发现进化上古老的管家相互作用组与较年轻的组织特异性模块之间的串扰受到系统性抑制。重连的蛋白质受到多种细胞机制的严格调控，并与疾病有关。我们的研究开辟了新途径，以揭示在哺乳动物系统中塑造体内相互作用组对生理和病理生理刺激反应的调控机制。
