Authors
Hélène Spangenberg, Emilie Løgith Moe, Øyvind Ødegård Fougner, Marte Sneeggen, Meng Pan, Kia Wee Tan, Maria Mateo Tortola, Camila Valenzuela, Yuen-Yan Chang, Harald Stenmark, Camilla Raiborg, Kay Oliver Schink
Published in
Journal of cell science. Oct 09, 2026. Epub Oct 09, 2026.
Abstract
Macropinocytosis is a non-selective endocytic process by which cells take up large amounts of extracellular fluid into giant vesicles known as macropinosomes. This mechanism is used by immune cells to sample the surroundings for antigens and can be exploited by cancer cells for nutrient uptake. What determines macropinosome fate after internalization is largely unknown. Here we investigate the role of the phosphatidylinositol 3-kinase VPS34/PIK3C3 and its product phosphatidylinositol 3-phosphate (PtdIns3P) in macropinosome fate determination. VPS34 inhibition reduced successful macropinosome maturation and fluid-phase uptake and prevented recruitment of early endosomal factors, including the small GTPase RAB5A and its effectors, to forming macropinosomes. Instead, forming macropinosomes under VPS34 inhibition accumulated regulators of endocytic recycling, including RAB8A, RAB10, RAB11A, and PtdIns4P, which led to fusion of macropinosomes with the plasma membrane. Whereas RAB5A was critical for establishment of endosomal identity, macropinosome fusion with the plasma membrane depended on RAB8A. Thus, macropinosome maturation is regulated by a VPS34-dependent phosphoinositide and RAB transition that determines whether newly formed macropinosomes acquire endosomal identity or recycle to the plasma membrane.
PMID:
42852846
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.
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