Secretory proteins are conventionally transported through the endoplasmic reticulum to the Golgi and then to the plasma membrane where they are released into the extracellular space. However, numerous substrates also reach these destinations using unconventional pathways. Unconventional protein secretion (UPS) is complex and comprises cargos without a signal peptide or a transmembrane domain that can translocate across the plasma membrane, and cargos that reach the plasma membrane by bypassing the Golgi despite entering the endoplasmic reticulum (ER). With a few exceptions, unconventional secretion is largely triggered by stress. Here I review new results and concepts that are beginning to define these pathways.
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