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

The secretory pathway processes >30% of mammalian proteins, orchestrating their synthesis, modification, trafficking, and quality control across multiple organelles via coordinated interactions, making its regulation difficult to decipher. To advance such research, we present secRecon, a reconstruction of the mammalian secretory pathway, comprising 1,127 manually curated genes organized within 77 secretory process terms, annotated with functional roles, subcellular localization, protein interactions, and complexes. Applying secRecon to omics data revealed distinct secretory topologies in antibody-producing plasma cells versus Chinese hamster ovary (CHO) cells, with CHO-specific deficiencies in proteostasis, translocation, and N-glycosylation genes, highlighting targets to enhance secretion. Analysis of single-cell SEC-seq data uncovered diversity in IgG-secreting plasma cells that is shaped by the unfolded protein response, endoplasmic reticulum (ER)-associated degradation, and vesicle trafficking and identified distinct secretory machinery genes as markers of plasma cell differentiation. These results show that secRecon enables the discovery of mechanisms controlling protein secretion and supports applications in both biomedical research and biotechnology. A record of this paper's transparent peer review process is included in the supplemental information.