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

Abstract

In mammals, >25% of proteins are synthesized and exported through the secretory pathway. The pathway complexity, however, obfuscates its impacts on the secretion of different proteins. Here we have mapped out the core biosynthetic proteins of the secretory pathway and integrate them with genome-scale metabolic models of human, mouse, and Chinese hamster ovary (CHO) cells. The resulting reconstructions RECON2.2s, iMM1685s, and iCHO2048s, enable the computation of the cost and machinery demanded by each secreted protein. We predicted metabolic costs and maximum productivities of biotherapeutics, and identified protein features that most significantly impact protein secretion. By integrating additional metabolomic, glycoproteomic and ribosomal profiling data, we further found that CHO cells have adapted to reduce expression and secretion of expensive host cell proteins. Finally, we are able to quantify improvements in protein production in CHO cells following efforts to eliminate unnecessary proteins. Our work represents a knowledge-base of the mammalian secretory pathway that serves as a novel tool for systems biotechnology. Support or Funding Information The Novo Nordisk Foundation through the Center for Biosustainability at the Technical University of Denmark (NNF10CC1016517 and NNF16CC0021858) and from the NIGMS (R35 GM119850) The core biosynthetic pathways of the mammalian secretory pathway have been mapped out and enable quantitative analysis using systems biology models. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.