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Secretory proteins exit the endoplasmic reticulum (ER) in coat protein complex II (COPII)-coated vesicles and then progress through the Golgi complex before delivery to their final destination. Soluble cargo can be recruited to ER exit sites by signal-mediated processes (cargo capture) or by bulk flow. For membrane proteins, a third mechanism, based on the interaction of their transmembrane domain (TMD) with lipid microdomains, must also be considered. In this Commentary, I review evidence in favor of the idea that partitioning of TMDs into bilayer domains that are endowed with distinct physico-chemical properties plays a pivotal role in the transport of membrane proteins within the early secretory pathway. The combination of such selforganizational phenomena with canonical intermolecular interactions is most likely to control the release of membrane proteins from the ER into the secretory pathway. [ABSTRACT FROM AUTHOR]

The Golgi complex and ER are dynamically connected by anterograde and retrograde trafficking pathways. To what extent and by what mechanism outward-bound cargo proteins escape retrograde trafficking has been poorly investigated. Here, we analysed the behaviour of several membrane proteins at the ER/Golgi interface in live cells. When Golgi-to-plasma membrane transport was blocked, vesicular stomatitis virus glycoprotein ( VSVG), which bears an ER export signal, accumulated in the Golgi, whereas an export signal-deleted version of VSVG attained a steady state determined by the balance of retrograde and anterograde traffic. A similar behaviour was displayed by EGF receptor and by a model tail-anchored protein, whose retrograde traffic was slowed by addition of VSVG's export signal. Retrograde trafficking was energy- and Rab6-dependent, and Rab6 inhibition accelerated signal-deleted VSVG's transport to the cell surface. Our results extend the dynamic bi-directional relationship between the Golgi and ER to include surface-directed proteins, uncover an unanticipated role for export signals at the Golgi complex, and identify recycling as a novel factor that regulates cargo transport out of the early secretory pathway. [ABSTRACT FROM AUTHOR]