Unconventional protein secretion triggered by nutrient starvation

It is usually assumed that eukaryotic cells secrete only proteins that contain a signal sequence for Sec61 mediated translocation into the lumen of endoplasmic reticulum (ER). Surprisingly however, many proteins, such as superoxide dismutase (SOD)1, acyl-CoA binding protein (Acb1), interleukin 1β, fibroblast growth factor 2 and the adipokine Unpaired2, to name a few, are secreted even though they lack a signal sequence. The discovery that these proteins are secreted has presented a new challenge and we describe here a common pathway by which SOD1 and Acb1 are specifically secreted upon nutrient starvation. Their secretion follows a type III unconventional pathway, requiring the exposure of a di-acidic motif, which we propose promotes their capture into a membrane compartment called CUPS (compartment for unconventional protein secretion). We suggest that CUPS, composed of membranes derived from the Golgi apparatus and endosomes, serves as a major sorting station prior to release of SOD1 and Acb1 into the extracellular space. The trafficking of these signal sequence lacking proteins therefore has functional similarities to conventional protein secretion in that they rely on membrane bounded compartments for their sorting and transport, but bypass the need of Sec61 for translocating into the ER and COPII and COPI for their intracellular transfers. This review is part of a Special Issue of SCDB on "unconventional protein secretion" edited by Walter Nickel and Catherine Rabouille.