macropinosomes

Macropinosomes are large endocytic vesicles formed during macropinocytosis, a clathrin-independent uptake pathway in which portions of the plasma membrane ruffle and enclose extracellular fluid and solutes. They are typically larger than vesicles formed by other endocytic routes, ranging from about 0.2 to several micrometers in diameter, and are common in macrophages, dendritic cells, and some epithelial and cancer cells.

Formation is driven by actin cytoskeleton rearrangements triggered by signaling through growth factor receptors and pattern-recognition receptors. Receptor engagement activates Rac1 and Cdc42, stimulating actin polymerization and the formation of membrane ruffles. Localized PI3K activity leads to accumulation of PIP3 and downstream effectors such as Pak1, promoting ruffle closure and vesicle scission from the plasma membrane. The resulting macropinosome non-specifically internalizes extracellular fluid and solutes.

Macropinosomes traffic through the endocytic pathway, often fusing with early endosomes and maturing to late endosomes and lysosomes. Some macropinosomes recycle membrane back to the plasma membrane. Cargo within macropinosomes can be degraded, processed for antigen presentation, or directed to metabolic pathways. In immune cells, macropinocytosis supports antigen sampling and can influence innate signaling, including TLR responses and cytokine production.

Physiological and pathological relevance varies by cell type. In immunity, macropinocytosis contributes to surveillance by dendritic cells and macrophages. In cancer, certain tumor cells upregulate macropinocytosis to acquire nutrients from extracellular protein, supporting growth under nutrient stress. Pathogens such as some viruses and bacteria can exploit macropinocytosis for cell entry. Inhibition of PI3K or Rac1 can suppress macropinocytosis, highlighting potential therapeutic implications.