Genome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion

Jahir M Gutierrez, Amir Feizi, Shangzhong Li, Thomas B Kallehauge, Hooman Hefzi, Lise Marie Grav, Daniel Ley, Deniz Baycin Hizal, Michael J Betenbaugh, Bjørn Gunnar Voldborg, Helene Faustrup Kildegaard, Gyun Min Lee, Bernhard O Palsson, Jens Nielsen, Nathan E Lewis*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.
Original languageEnglish
Article number68
JournalNature Communications
Volume11
Issue number1
ISSN2041-1723
DOIs
Publication statusPublished - 2020

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