Abstract
One third of all proteins in eukaryotes transit between the endoplasmic reticulum (ER) and the Golgi to reach their functional destination inside or outside of the cell. During export, secretory proteins concentrate at transitional zones of the ER known as ER exit sites, where they are packaged into transport carriers formed by the highly conserved coat protein complex II (COPII). Despite long-standing knowledge of many of the fundamental pathways that govern traffic in the early secretory pathway, we still lack a complete mechanistic model to explain how the various steps of COPII-mediated ER exit are regulated to efficiently transport diverse cargoes. In this Review, we discuss the current understanding of the mechanisms underlying COPII-mediated vesicular transport, highlighting outstanding knowledge gaps. We focus on how coat assembly and disassembly dictate carrier morphogenesis, how COPII selectively recruits a vast number of cargo and cargo adaptors, and finally discuss how COPII mechanisms in mammals might have adapted to enable transport of large proteins.
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Acknowledgements
Work in the group of G.Z. was supported by the European Research Council (ERC-StG-2019 grant 852915) and the Biotechnology and Biological Sciences Research Council (BBSRC grant BB/T002670/1).
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Supplementary information
Glossary
- Arginine finger
-
This is a highly conserved and essential residue acting in trans on many GTPase and AAA+ ATPase enzymes to promote GTP hydrolysis. Often they are found in GTPase-activating proteins (GAPs) (such as Sec23).
- Bulk flow
-
Bulk flow refers to the passive export of proteins at their prevailing concentrations within the endoplasmic reticulum.
- Chylomicrons
-
Chylomicrons are large lipoproteins produced in enterocytes. They are composed of a central lipid core primarily consisting of triglycerides, together with esterified cholesterol and phospholipids and transport dietary fat from the intestine to the liver and peripheral tissues.
- Cryo-structured illumination microscopy
-
Interference-based high-resolution fluorescence technique performed at cryogenic temperatures (below −160 °C).
- Focused ion beam–scanning electron microscopy
-
A dual beam technique where scanning electron microscopy is combined with a focussed ion beam to visualize and mill material. It can be used to prepare thin lamellae of biological samples for use in transmission electron microscopy, or to produce serial scanning electron microscopy images of the ‘face’ of the block being milled.
- Giant unilamellar vesicles
-
Spherical particles made of a lipid bilayer with sizes in the micrometre range. They can be used to mimic cellular membranes for in vitro experiments.
- Microsomes
-
Particles derived from permeabilised cells after differential centrifugation, consisting mostly of endoplasmic reticulum membranes.
- Molecular dynamics simulations
-
A computational technique used to simulate the physical movements of atoms and molecules over time based on their energy landscape.
- Retention using selective hooks
-
The retention using selective hooks (RUSH) system is used to synchronise protein transport within the secretory pathway. It consists of a ‘hook’ (a streptavidin-tagged protein localized to a secretory compartment like the endoplasmic reticulum) and a ‘reporter’ (a fluorescently tagged protein fused to streptavidin binding peptide, SBP). The streptavidin-SBP interaction retains the reporter at the location of the hook, and is disrupted by biotin, causing the reporter to be released synchronously.
- Tryptophan fluorescence measurements
-
A technique that monitors tryptophan fluorescence to measure conformational changes in proteins.
- v-SNARE
-
SNAREs mediate the fusion of vesicles with the target membrane via the interaction of vesicle localized SNAREs (v-SNAREs) with target membrane localized SNAREs (t-SNAREs).
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Downes, K.W., Zanetti, G. Mechanisms of COPII coat assembly and cargo recognition in the secretory pathway. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00839-y
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DOI: https://doi.org/10.1038/s41580-025-00839-y
