Unconventional protein secretion (known as ER/Golgi-independent protein secretion or nonclassical protein export^[1] ) represents a manner in which the proteins are delivered to the surface of plasma membrane or extracellular matrix independent of the endoplasmic reticulum or Golgi apparatus.^[2] This includes cytokines and mitogens with crucial function in complex processes such as inflammatory response or tumor-induced angiogenesis. Most of these proteins are involved in processes in higher eukaryotes, however an unconventional export mechanism was found in lower eukaryotes too.^[3] Even proteins folded in their correct conformation can pass plasma membrane this way, unlike proteins transported via ER/Golgi pathway.^[1] Two types of unconventional protein secretion are these: signal-peptid-containing proteins and cytoplasmatic and nuclear proteins that are missing an ER-signal peptide (1).^[2]

These proteins contain a specific signal-peptide sequence, which is to be translated into the endoplasmic reticulum, but are, however, able to reach the cell surface unconventionally. They can be packed into a COPII-coated vesicle and directly fuse with plasma membrane or can fuse with endosomal or lysosomal compartment. Alternatively, they can be packed into non-COPII-coated vesicle as well and fuse with Golgi (before reaching plasma membrane) or directly delivered to the plasma membrane.^[2]

Soluble proteins can reach the surface of the cell both by non-vesicular and vesicular mechanisms. Non-vesicular mechanisms use a carrier to get proteins into extracellular space (for example phosphatidylinositol-4,5-bisphosphate). Vesicular mechanisms can use the lysosome-dependent pathway, microvesicle shedding or biogenesis of multivesicular bodies.^[2]