Fig. 2: Schematic representation of proteasome secretory pathways.

Unlike classic protein secretion involving ER-to-Golgi transport, cytosolic proteasomes are expected to be directed to the extracellular space through unconventional secretory pathways. Under stress or pathological conditions, the 26S proteasome dissociates into 20S and 19S particles, and simultaneously, de novo synthesis of the 20S immunoproteasome may be induced. The 20S forms of proteasomes can be released through microvesicle shedding (route 1). Alternatively, the 20S forms of proteasomes are first packaged into endocytic compartments, such as multivesicular bodies and autophagosomes (routes 2 and 3, respectively), which later fuse with the plasma membrane and are then released as exosomes. The level and activity of 20S c-proteasomes can be readily detected using ELISA and fluorogenic reporter peptides, respectively. The physiological and pathological significance of these pathways remains to be investigated.