Genome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion
Journal article, 2020

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.

Author

Jahir M. Gutierrez

University of California

Amir Feizi

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Shangzhong Li

University of California

Thomas B. Kallehauge

Technical University of Denmark (DTU)

Hooman Hefzi

University of California

Lise M. Grav

Technical University of Denmark (DTU)

Daniel Ley

Technical University of Denmark (DTU)

Deniz Baycin Hizal

Turgut Illaclari A.S

Michael J. Betenbaugh

Johns Hopkins University

Bjørn G. Voldborg

Technical University of Denmark (DTU)

Helene Faustrup Kildegaard

Technical University of Denmark (DTU)

Gyun Min Lee

Technical University of Denmark (DTU)

B. O. Palsson

Technical University of Denmark (DTU)

University of California

Jens B Nielsen

Technical University of Denmark (DTU)

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Nathan E. Lewis

University of California

Nature Communications

2041-1723 (ISSN)

Vol. 11 1 68

Subject Categories

Biochemistry and Molecular Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Bioinformatics and Systems Biology

DOI

10.1038/s41467-019-13867-y

PubMed

31896772

More information

Latest update

4/16/2020