Genome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion
Genome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion
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DOI：
10.1038/s41467-019-13867-y
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发表时间：
2020-01-02
影响因子：
16.6
通讯作者：
Lewis, Nathan E.
中科院分区：
文献类型：
--
作者：
Gutierrez, Jahir M.;Feizi, Amir;Lewis, Nathan E.
在哺乳动物细胞中，25%的合成蛋白质是通过分泌途径输出的。然而，途径的复杂性混淆了它对不同蛋白质分泌的影响。揭示其对不同蛋白质的影响对生物制药生产尤为重要。在这里，我们描绘了核心的分泌途径功能，并将它们与人、小鼠和中国仓鼠卵巢细胞的基因组规模的代谢重建相结合。由此产生的重建能够计算每种分泌蛋白质的能量成本和机械需求。通过整合额外的组学数据，我们发现高分泌细胞已经适应了减少其他昂贵宿主细胞蛋白的表达和分泌。此外，我们还预测了生物治疗性蛋白质的代谢成本和最大生产率，并确定了对蛋白质分泌影响最大的蛋白质特征。最后，该模型成功地预测了在沉默高表达的选择标记后单抗的分泌增加。这项工作代表了哺乳动物分泌途径的知识库，作为系统生物技术的新工具。
In mammalian cells, >25% of synthesized proteins are exported through the secretory pathway. The pathway complexity, however, obfuscates its impact on the secretion of different proteins. Unraveling its impact on diverse proteins is particularly important for biopharmaceutical production. Here we delineate the core secretory pathway functions and integrate them with genome-scale metabolic reconstructions of human, mouse, and Chinese hamster ovary cells. The resulting reconstructions enable the computation of energetic costs and machinery demands of each secreted protein. By integrating additional omics data, we find that highly secretory cells have adapted to reduce expression and secretion of other expensive host cell proteins. Furthermore, we predict metabolic costs and maximum productivities of biotherapeutic proteins and identify protein features that most significantly impact protein secretion. Finally, the model successfully predicts the increase in secretion of a monoclonal antibody after silencing a highly expressed selection marker. This work represents a knowledgebase of the mammalian secretory pathway that serves as a novel tool for systems biotechnology.