ArticleProceedings of the National Academy of Sciences of the United States of America2025
Deciphering the determinants of recombinant protein expression across the human secretome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Improving recombinant protein productivity in CHO cells via multi-omics data integration.Bioresources and bioprocessing · 2026Review
- From Mechanistic Interpretability to Mechanistic Biology: Training, Evaluating, and Interpreting Sparse Autoencoders on Protein Language Models.bioRxiv : the preprint server for biology · 2025Article
- Artificial intelligence-driven systems engineering for next-generation plant-derived biopharmaceuticals.Frontiers in plant science · 2023Review
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
Protein secretion is an essential process of mammalian cells. In biomanufacturing, this process can be optimized to enhance production yields and biotherapeutic quality. While cell line engineering and bioprocess optimization have yielded high protein titers for some recombinant proteins, many remain difficult to express. Here, we investigated factors influencing protein expression in Chinese hamster ovary (CHO) cells, expressing 2,135 Human Secretome Project proteins. While the abundance of mRNA from recombinant proteins explained less than 1% of observed variation in secretion titers, analysis of 218 biochemical and biophysical descriptors uncovered intrinsic protein features that account for ~15% of secretion variability, pinpointing key drivers such as molecular weight, cysteine content, and N-linked glycosylation, and establishing a roadmap for rational design of difficult-to-express proteins. We subsequently analyzed RNA-Seq data from 95 CHO cell cultures, each expressing a distinct recombinant protein, spanning a wide range of titers. Host cell transcriptomic signatures showed strong correlations with titer, thereby providing insights into cellular processes that covary with expression. Cells failing to produce proteins exhibited increased ubiquitin-mediated proteasomal degradation, including ER-associated degradation; whereas high-producing cells demonstrated enhanced lipid metabolism and a stronger response to oxidative stress, suggesting these factors may support successful recombinant protein productions. Together, using this resource, we quantified the contributions of various protein and cellular factors that correlate with the expression of diverse recombinant human proteins in a heterologous host, thereby providing insights for next-generation CHO cell engineering.
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