Figures & data
Figure 1. A schematic model of HPSE trafficking and function in autophagy. Once secreted (1), HPSE rapidly interacts with cell membrane HSPGs such as SDC/syndecans (2), followed by rapid endocytosis of the HPSE-HSPG complex (3). Conversion of endosomes to lysosomes (4) results in HPSE processing and activation (5). Typically, HPSE appears at perinuclear lysosomal vesicles (5 and middle lower image). Lysosomal HPSE drives fusion with autophagosomes and controls the basal levels of autophagy. Cancer cells that exhibit a high content of HPSE (HPSE-high) are endowed with increased levels of autophagy (6 and left vs. right lower electron micrographs) that promote tumor growth and chemoresistance. Enhanced autophagy by HPSE is associated with reduced RPS6KB phosphorylation levels and accumulation of MTORC1 at perinuclear areas (7) vs. a more diffuse distribution in control (HPSE-low) cells. This function of HPSE within the cell encourages the development of a new class of inhibitors that will prevent HPSE uptake and lysosomal accumulation (8). HS, heparan sulfate; mAb, monoclonal antibody.
