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First published online 31 October 2006
doi: 10.1242/jcs.03238

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Macropinocytosis: regulated coordination of endocytic and exocytic membrane traffic events

Sestina Falcone^1,2,*, Emanuele Cocucci^3,*, Paola Podini², Tomas Kirchhausen⁴, Emilio Clementi^1,2 and Jacopo Meldolesi^2,3,5,

¹ University of Milan, Department of Preclinical Sciences, via G.B. Grassi 74, 20157 Milan, Italy, and E. Medea Scientific Institute, 23842 Bosisio Parini, Italy
² Scientific Institute San Raffaele, Stem Cell Research Institute
³ Vita-Salute San Raffaele University, Department of Neuroscience, Center of Excellence on Cell Development, via Olgettina 58, 20132 Milan, Italy
⁴ Harvard Medical School, The CBR Institute for Biomedical Research, Longwood Avenue, Boston, MA 02115, USA
⁵ IIT Research Unit of Molecular Neuroscience, via Olgettina 58, 20132 Milan, Italy

Author for correspondence (e-mail: meldolesi.jacopo{at}hsr.it)

Accepted 31 August 2006

Macropinocytosis, a form of bulk uptake of fluid and solid cargo into cytoplasmic vacuoles, called macropinosomes, has been studied mostly in relation to antigen presentation. Early membrane traffic events occurring in this process are, however, largely unknown. Using human dendritic cells we show that a marked increase in the rate of macropinocytosis occurs a few minutes after application of two markers (small latex beads or dextran), depends on a slow intracellular Ca2⁺ concentration ([Ca²⁺]_i) rise that precedes the PI3K-dependent step, and is preceded and accompanied by exocytosis of enlargeosomes compensating in part for the macropinocytic plasma membrane internalization. Unexpectedly, macropinosomes themselves, which share markers with endosomes, undergo Ca²⁺-dependent exocytosis so that, after 20 minutes of continuous bead or dextran uptake, an equilibrium is reached preventing cells from overloading themselves with the organelles. Large [Ca²⁺]_i increases induced by ionomycin trigger rapid (<1 minute) exocytic regurgitation of all macropinosomes, whereas endosomes remain apparently unaffected. We conclude that, in dendritic cells, the rate of macropinocytosis is not constant but increases in a regulated fashion, as previously shown in other cell types. Moreover, macropinosomes are not simple containers that funnel cargo to an endocytic pathway, but unique organelles, distinct from endosomes by their competence for regulated exocytosis and other membrane properties.

Key words: Macropinocytosis, Regulated exocytosis, Membrane traffic, Dendritic cells, Enlargeosomes

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