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

作者：Helen O. Masson, Jasmine Tat, Pablo Di Giusto, Athanasios Antonakoudis, Isaac Shamie, Hratch Baghdassarian, Mojtaba Samoudi, Caressa M. Robinson, Chih-Chung Kuo, Natália Massaco Koga, Sonia Singh, Angel Gezalyan, Zerong Li, Alexia Movsessian, Anne Richelle, Nathan E. Lewis · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.11.14.623668 · 被引用次数：4 · 研究领域：Galectins and Cancer Biology、Glycosylation and Glycoproteins Research、Monoclonal and Polyclonal Antibodies Research

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 dif...