The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer^1,2,3. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.

细胞生长和分裂的细胞周期是生命的基本过程。它的失调会带来毁灭性的后果，包括癌症^1,2,3. 细胞周期是由蛋白质在时间和空间上的精确调节驱动的，这会在单个增殖细胞之间产生变异性。据我们所知，不存在对这种细胞间蛋白质组学变异性的系统研究。在这里，我们通过将亚细胞分辨率的蛋白质组学与单细胞转录组学和细胞周期中单个细胞的精确时间测量相结合，展示了人类蛋白质组异质性的综合时空图。我们表明，大约五分之一的人类蛋白质组显示出细胞间的变异性，识别出数百种与有丝分裂和细胞周期有以前未知关联的蛋白质，并提供了这些蛋白质中的几种具有致癌功能的证据。我们的结果表明，细胞周期进程解释了所有细胞间变异性的不到一半，并且大多数循环蛋白在翻译后进行调节，而不是通过转录组循环进行调节。这些蛋白质被调节细胞命运的激酶不成比例地磷酸化，而细胞之间不同的非循环蛋白更可能被调节新陈代谢的激酶修饰。这种空间分辨的细胞周期蛋白质组学图谱被整合到人类蛋白质图谱中，并将作为加速人类细胞周期和细胞增殖分子研究的资源。