Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type–protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine–homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

分泌的多肽是细胞间和内分泌通讯的基本轴。然而，对完整哺乳动物生物体中细胞分泌体的组成和动力学的全面了解一直缺乏。在这里，我们介绍了一种邻近生物素化策略，该策略能够以细胞类型选择性的方式在小鼠中标记、检测和富集分泌的多肽。我们通过直接从血浆中纯化生物素化的分泌蛋白，生成了肝细胞、肌细胞、周细胞和骨髓细胞分泌蛋白组的蛋白质组图谱。我们的分泌蛋白组数据集验证了已知的细胞类型-蛋白质对，揭示了区分细胞类型的分泌多肽，并识别了经典血浆蛋白的新细胞来源。最后，我们发现了肝细胞分泌蛋白组的动态且以前未描述的营养依赖性重编程，其特征是细胞溶质酶甜菜碱-同型半胱氨酸 S-甲基转移酶 (BHMT) 的非常规分泌增加。这种分泌蛋白组分析策略能够动态和细胞类型特异性地剖析血浆蛋白质组和介导细胞间信号传导的分泌多肽。