Revisiting secretory granule fusion at vesicular pseudopodia

Secretory granules are specialized vesicles that package large amounts of cargo, such as hormones, enzymes and mucous. They are typically stored intracellularly until an extracellular signal initiates exocytosis, characterized by fusion between the secretory vesicles and the plasma membrane, resulting in cargo release to the environment. Observations made in the 1970s suggested that some secretory granules project a pseudopodium from their surface where fusion with the cell surface occurs. However, these observations fell into obscurity, leaving the mechanistic and physiological significance of vesicular pseudopodia unknown. This knowledge gap prompted us to consolidate the current knowledge on pseudopodia and exocytosis, which has led us to the hypothesis that pseudopodia are an evolutionarily conserved adaptation of large secretory granules important for efficient fusion and cargo release. In this Perspective, we aim to reignite interest in elucidating the mechanisms governing pseudopodia structure and function in the context of the unique challenges faced by secretory tissues utilizing large secretory granules.