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PreprintCited by 6Cellular transport and secretionBioinformatics and Genomic NetworksEndoplasmic Reticulum Stress and Disease

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A reconstruction of the mammalian secretory pathway identifies mechanisms regulating antibody production

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Masson, Helen, Tat, Jasmine, Di Giusto, Pablo, Antonakoudis, Athanasios, Shamie, Isaac, Baghdassarian, Hratch, Samoudi, Mojtaba, Robinson, Caressa M., Kuo, Chih-Chung, Koga, Natalia, Singh, Sonia, Gezalyan, Angel, Li, Zerong, Movsessian, Alexia, Richelle, Anne, Lewis, Nathan E.·2024·Cell Systems
DOI 10.1101/2024.11.14.623668PMC PMC12704830

Preprint — published as 10.1016/j.cels.2025.101453 · Paper page

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Abstract

The secretory pathway processes >30% of mammalian proteins, orchestrating their synthesis, modification, trafficking, and quality control. However, its complexity— spanning multiple organelles and dependent on coordinated protein interactions—limits our ability to decipher how protein secretion is controlled in biomedical and biotechnological applications. To advance such research, we present secRecon—a comprehensive reconstruction of the mammalian secretory pathway, comprising 1,127 manually curated genes organized within an ontology of 77 secretory process terms, annotated with functional roles, subcellular localization, protein interactions, and complex composition. Using secRecon to integrate multi-omics data, we identified distinct secretory topologies in antibody-producing plasma cells compared to CHO cells. Genes within proteostasis, translocation, and N-glycosylation are deficient in CHO cells, highlighting them as potential engineering targets to boost secretion capacity. Applying secRecon to single-cell transcriptomics and SEC-seq data, we uncovered secretory pathway signatures underlying secretion diversity among IgG-secreting plasma cells. Different transcriptomic clusters had unique secretory phenotypes characterized by variations in the unfolded protein response (UPR), endoplasmic reticulum-associated degradation (ERAD), and vesicle trafficking pathways. Additionally, we discovered specific secretory machinery genes as new markers for plasma cell differentiation. These findings demonstrate secRecon can identify mechanisms regulating protein secretion and guide diverse studies in biomedical research and biotechnology. Graphical Abstract:

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Metadata

Authors
Masson, H., Tat, J., Di Giusto, P., Antonakoudis, A., Shamie, I., Baghdassarian, H., Samoudi, M., Robinson, C. M., Kuo, C.-C., Koga, N., Singh, S., Gezalyan, A., Li, Z., Movsessian, A., Richelle, A., & Lewis, N. E.
Affiliations
  • University of California San Diego (US)
  • Sartorius (United Kingdom) (GB)
  • University of Georgia (US)
Corresponding author
Lewis, Nathan E.
ORCID
Venue
Cell Systems
Publisher
openRxiv
Published
2024-11-15
Volume
16
Issue
12
Pages
101453-101453
ISSN
2405-4712 (ISSN-L)
DOI
10.1101/2024.11.14.623668
PMC
PMC12704830
OpenAlex
W4417198380
Cited by
6
References
1
Citations by year
2026: 4 · 2025: 2
FWCI
2.97
Type
journal article
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Cell Systems (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • National Science Foundation (2030039)
  • Novo Nordisk Fonden (NNF20SA0066621)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R35GM119850)
  • National Institute of Allergy and Infectious Diseases (UH2AI153029)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
secretory pathway, protein secretion, antibody production, plasma cells, gene ontology annotation, N-glycosylation, proteostasis, unfolded protein response, ER-associated degradation, vesicle trafficking, plasma cell differentiation, CHO cells, protein quality control
MeSH terms
Animals, Antibody Formation, Cricetulus, Endoplasmic Reticulum, Humans, Mammals, Plasma Cells, CHO Cells, Protein Transport, Secretory Pathway, Unfolded Protein Response

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