The Post Office Inside Your Cells: Secretion vs. Membrane Delivery

When the topic of what determines whether proteins from the rough ER are destined for secretion or to be incorporated into the plasma membrane was discussed in class, it was mentioned we were not fully sure. I decided to delve further into this to see if there is an explanation. As mentioned in class, proteins need a signal peptide pre-sequence on the N terminus to leave the ER and travel to the Golgi. From there, the deciding factor is whether or not the protein has a transmembrane domain (TMD), which is not something added later but rather encoded in the gene and made during translation at the rough ER. These TMDs are stretches of about 20–25 hydrophobic amino acids that the Sec61 translocon recognizes, inserting them laterally into the lipid bilayer so the protein becomes an integral membrane protein¹. In contrast, proteins that have only a cleavable N-terminal signal peptide and lack TMDs are fully translocated into the ER lumen, carried through the Golgi, and eventually secreted, as is the case for insulin².

The Golgi then acts like a sorting hub. Proteins arrive already set as soluble or membrane-bound from the ER, but the Golgi decides where they go next. Secreted proteins, such as insulin, stay in the lumen of the cisternae, where they are modified by glycosylation and cleavage. At the trans-Golgi network (TGN), they are packed into constitutive secretory vesicles, which release continuously, or into regulated vesicles, which hold onto their contents until a signal like rising blood glucose tells them to release². Plasma membrane proteins, including receptors, ion channels, and GPCRs, keep their TMDs embedded in the Golgi membrane as they pass through the cisternae³. At the TGN, they are sorted into transport vesicles that fuse with the plasma membrane. When this happens, their TMDs remain locked in the lipid bilayer, integrating the proteins into the structure of the cell surface³. At the core of it, TMDs decide whether proteins are secreted or become part of the membrane. The fact that our cells perform this level of choreography every second is nothing short of amazing!

References

1    Xin, J., Yin, K., Li, S., Gu, P., & Shao, S. (2025). Exploring the ER channel protein Sec61: recent advances in pathophysiological significance and novel pharmacological inhibitors. Frontiers in pharmacology, 16, 1580086. https://doi.org/10.3389/fphar.2025.1580086

2.     Štepihar, D., Florke Gee, R. R., Hoyos Sanchez, M. C., & Fon Tacer, K. (2023). Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion. Frontiers in cell and developmental biology, 11, 1243038. https://doi.org/10.3389/fcell.2023.1243038

3.     Anup Parchure, & Blume, J. von. (2023). Sorting secretory proteins. ELife, 12. https://doi.org/10.7554/elife.93490