Trends in Cell Biology
OpinionEndocytosis without clathrin coats
Section snippets
Diversity and roles of clathrin-independent pathways
A variety of endocytic pathways that do not utilize clathrin are responsible for taking up either large particles or small solutes, together with membrane, into cells. These pathways include phagocytosis, caveolae-mediated uptake, macropinocytosis and constitutive non-clathrin uptake. Phagocytosis is the process whereby large particles are internalized by cells. Uptake is typically triggered by binding of the particle to cell-surface receptors capable of transducing a phagocytic stimulus. This
Caveolar uptake
Caveolae are flask shaped, non-coated plasma membrane invaginations present in many cell types, but are especially abundant in endothelial cells, where they are implicated in transcytosis and endocytosis of blood components (see Fig. 1). Biochemically, caveolae are characterized by their association with a family of cholesterol-binding proteins called caveolins, which function to create and/or maintain these structures 12. Consistent with this, expressing caveolin in cells that do not normally
Macropinocytosis
Macropinocytosis refers to the formation of large, irregular primary endocytic vesicles by the closure of lamellipodia generated primarily at ruffling membrane domains. Macropinosomes are dynamic structures, frequently moving inwards towards the centre of the cell, and persist for approximately 5–20 min (Ref. 18). The membrane components of macropinosomes are likely to be recycled back to the plasma membrane over a similar time-scale, potentially passing via other organelles within the cell,
Constitutive clathrin-independent endocytosis
Macropinosomes are typically associated with ruffling membrane and not often found in resting, unstimulated cells. However, even in unstimulated cells, there are likely to be constitutive clathrin-independent endocytic pathways, as described in several recent papers 6, 7, 11. Lamaze et al.11 found that endocytosis of interleukin 2 (IL-2) receptors proceeded normally in cells where clathrin function was disrupted by use of eps15 mutants. Eps15 binds directly to the plasma membrane adaptor AP-2
Bacterial toxins as markers for clathrin-independent endocytosis
Several bacterial toxins enter the cell by binding to cell-surface receptors, being endocytosed, and ultimately translocating into the cytosol from an intracellular compartment. A number of these toxins are taken up independently of clathrin and hence provide valuable markers 37. However, the diversity of endocytic pathways and potential for simultaneous uptake through multiple routes frequently makes interpreting the literature complex. A case in point is provided by perhaps the best-studied
Non-clathrin endocytosis and lipid rafts
Given the ubiquity and diversity of clathrin-independent uptake pathways, an important conclusion must be that the coated-vesicle paradigm is far from the only way in which cells have solved the problem of transporting material between different organelles while maintaining the specific membrane composition of each individual organelle. Partitioning into putative microdomains on the plasma membrane, or rafts, offers an attractive explanation for how sorting into clathrin-independent uptake
Concluding remarks
In this article, we have highlighted the diversity of endocytic pathways found within mammalian cells, and argued that clathrin-independent endocytosis is likely to play an important role in membrane dynamics and in remodeling of the plasma membrane in response to external stimuli. The most obvious challenges for the future are to provide a better description of the molecular machinery that mediates these pathways and to better characterize their spatial and temporal regulation.
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