Endolysosomal Pathways and Exosome Secretion in Pancreatic Acinar Cells: Mechanisms of Secretory Polarity and Vesicle Trafficking

Abstract

Pancreatic acinar cells are essential for digestive processes, synthesizing and secreting enzyme-rich zymogen granules (ZGs) via highly regulated exocytosis. Maintaining apical-basolateral polarity is essential to prevent premature enzyme activation and the onset of pancreatitis. While the traditional ZG pathway has historically been regarded as the primary mechanism of enzyme secretion, both the constitutive-like pathway (CLP) and the minor regulated pathway (MRP) serve crucial roles in ZG maturation. These endolysosomal routes facilitate the removal of lysosomal hydrolases, the enrichment of nascent proteases, and are selectively inhibited by brefeldin A (BFA) without impacting mature ZGs. Moreover, the CLP/MRP are required for efficient ZG exocytosis, with Tumor Protein D52 (TPD52 or D52) being a pivotal molecular component of both pathways. Tumor protein D52 is highly expressed in secretory epithelia and undergoes Ca2+-dependent phosphorylation, facilitating its translocation from endolysosomal compartments to apical membranes. This process underpins the sorting and targeting of digestive enzymes to the apical surface via the CLP/MRP pathway. Disruption in D52 expression or its phosphorylation impairs subapical endolysosomal platforms, leading to mis-sorting of enzymes to the basolateral membrane and an increased vulnerability to pancreatic injury. SNARE proteins, including VAMP2, VAMP8, syntaxins, and SNAPs, facilitate membrane fusion within both the ZG and endolysosomal pathways. The complexes formed by VAMP2, Syntaxin2, and Complexin2 initiate the early stage of regulated secretion, whereas changes in SNARE localization are linked to spatial dysregulation and the progression of disease. Rab11a, a regulator of apical recycling endosomes, colocalizes with D52 within subapical compartments, establishing a coordinated trafficking system with SNAREs that sustains polarity and regulates exocytosis. Recent evidence indicates that a subset of D52 is integrated into multivesicular bodies (MVBs) and subsequently released via exosomes. This is corroborated by the enrichment of D52, TSG101, and Rab27a in highly purified exosomal fractions derived from stimulated acini. Such findings extend the functional scope of D52 beyond intracellular maturation, suggesting a potential role in intercellular signaling during pancreatic inflammation. This thesis clarifies the roles of D52, SNAREs, and Rab11a in vesicle trafficking, secretory polarity, and granule refinement. It explores their molecular interactions and regulation, creating a foundation for understanding trafficking defects in pancreatitis and highlighting D52 as a key link between polarity maintenance and disease development.