Beyond ER-Golgi trafficking: unconventional protein secretion as a new design frontier for synthetic secretion switches in mammalian cells.

Authors

Bingshun Shi, Xinyuan Qiu, Yongheng Jiang, Jiabo Cai, Lingyun Zhu

Published in

Communications biology. Volume 9. Issue 1. Sep 19, 2026. Epub Sep 19, 2026.

Abstract

Mammalian gene switches enable programmable cell behavior. However, current switches on transcriptional and translational layers require de novo RNA and protein synthesis, and secreted outputs must additionally undergo folding, post-translational processing, and intracellular trafficking, imposing delays that limit rapid extracellular responses. Rapid secretion-control switches instead act on pre-synthesized proteins by controlling retention, trafficking, storage, or release. Most current platforms exploit the classical endoplasmic reticulum (ER)-Golgi pathway, including engineered stimulus-secretion coupling in specialized secretory cells and ER retention, retrieval-signal cleavage, or synchronized trafficking in general mammalian hosts. Although these strategies improve response kinetics, they remain limited by ER dependence, host-cell specificity, cargo compatibility, basal leakage, and post-release transport delays. Here, we review current secretion-control architectures and highlight unconventional protein secretion as an underexplored source of design principles for positioning regulatory control closer to terminal protein export and expanding the architectures available for mammalian secretion control.

PMID:
42763312
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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