Reticulon 4a promotes exocytosis in mammalian cells

Endoplasmic reticulum (ER) tubules and sheets conventionally correspond to smooth and rough ER, respectively. The ratio of ER tubules-to-sheets varies in different cell types and changes in response to cellular conditions, potentially impacting the functional output of the ER. To directly test whether ER morphology impacts vesicular trafficking, we increased the tubule-to-sheet ratio in three different ways, by overexpressing Rtn4a, Rtn4b, or REEP5. Only Rtn4a overexpression increased exocytosis, but not overall levels, of several cell surface and secreted proteins. Furthermore, Rtn4a depletion reduced cell surface trafficking without affecting ER morphology. Similar results were observed in three different mammalian cell lines, suggesting that Rtn4a generally enhances exocytosis independently of changes in ER morphology. Finally, we show that Rtn4a levels modulate cell adhesion, possibly by regulating trafficking of integrins to the cell surface. Taking the results together, we find that altering ER morphology does not necessarily affect protein trafficking, but that Rtn4a specifically enhances exocytosis.