Glycosylation Triggers Cathepsin D Maturation and Secretion to Promote Gastric Cancer Development

Cathepsin D (CTSD) is a lysosomal aspartic protease with high expression in cancers. CTSD localized in different subcellular regions performs distinct roles. However, the precise regulation of its intracellular trafficking and extracellular secretion remains incompletely understood. This study showed that glycosylation modifications of CTSD determined its maturation and secretion in gastric cancer (GC) cells. Specifically, glycosylation at asparagine 134 (N134) dictated the intracellular trafficking and maturation of CTSD within lysosomes, through facilitating its sorting into COPII vesicles. Glycosylation at asparagine 263 (N263) was essential for the secretion of the proenzyme form of CTSD (pro-CTSD) via a novel pathway dependent on the small GTPase Rab3D. Notably, the extracellular release of pro-CTSD occurred more rapidly than its intracellular trafficking from the endoplasmic reticulum to lysosomes. This enhanced secretion speed may rapidly elevate the levels of pro-CTSD in the tumor microenvironment in response to extracellular stimuli. Ultimately, glycosylation at N134 and N263 regulated the autophagy and cell proliferation, respectively. These findings show the role of glycosylation in triggering the maturation and secretion of CTSD in GC cells. Through modulating its cellular trafficking, differential glycosylation modifications of CTSD defined the malignant behavior of GC cells.