Fast and ultrafast endocytosis

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Highlights

  • Reaction to stress, chemotaxis or synaptic vesicle exocytosis requires fast endocytosis.

  • Clathrin-mediated endocytosis may be too slow to regulate fast physiological responses.

  • Several fast clathrin-independent endocytic processes have been identified.

  • Ultrafast endocytosis mediates rapid membrane removal at synapses.

  • Fast-endophilin-mediated endocytosis (FEME) is triggered upon receptor activation.

Clathrin-mediated endocytosis (CME) is the main endocytic pathway supporting housekeeping functions in cells. However, CME may be too slow to internalize proteins from the cell surface during certain physiological processes such as reaction to stress hormones (‘fight-or-flight’ reaction), chemotaxis or compensatory endocytosis following exocytosis of synaptic vesicles or hormone-containing vesicles. These processes take place on a millisecond to second timescale and thus require very rapid cellular reaction to prevent overstimulation or exhaustion of the response. There are several fast endocytic processes identified so far: macropinocytosis, activity-dependent bulk endocytosis (ABDE), fast-endophilin-mediated endocytosis (FEME), kiss-and-run and ultrafast endocytosis. All are clathrin-independent and are not constitutively active but may use different molecular mechanisms to rapidly remove receptors and proteins from the cell surface. Here, we review our current understanding of fast and ultrafast endocytosis, their functions, and molecular mechanisms.

Introduction

Endocytosis is essential for all eukaryotic cells to internalize macromolecules and proteins such as receptors, channels and transporters from plasma membrane. Endocytosis controls the levels of receptors at the cell surface and thereby regulates their signaling [1]. It also mediates synaptic vesicle recycling to support the rapid recovery of vesicle pools following synaptic transmission [2•, 3]. Internalized receptors (also referred to as endocytic ‘cargoes’) are sorted in endosomes for recycling back to the plasma membrane to sustain signaling or for degradation in lysosomes to induce long-term desensitization of the cell [4, 5]. Many viruses and bacterial toxins exploit endocytosis to gain access into eukaryotic cells and infect or poison cells [6, 7]. There are several pathways of endocytosis, defined by their distinct morphological features or by their requirement of key cytosolic components. Clathrin-mediated endocytosis (hereafter, CME) is the best characterized endocytic pathway and supports the uptake of a wide range of cell surface proteins [1, 8]. In CME, cargo receptors are sorted by adaptor proteins that bridge them to clathrin triskelia. Clathrin then polymerizes into ‘soccer ball’ looking coats during the formation of endocytic pits [8]. All other endocytic pathways are referred to as clathrin-independent endocytosis (CIE) [1, 9•]. Each CIE pathway is typically named after its morphology (coat-less invaginations emanating from the plasma membrane), cytosolic proteins markers or cargoes (such as viruses, IL2Rβ, MHC class I, CD44 or Shiga toxin [10, 11, 12, 13, 14, 15]). However, some CIE do not appear to have specific cargoes or markers and can only be identified by morphology (macropinocytosis).

Compared to CME, our understanding of CIE is lagged likely because (i) these pathways are typically not constitutive and only activated upon specific stimuli, (ii) molecular players may not be specific to the CIE pathways and (iii) some CIE events might be too fast to be recorded by classical methods used to study endocytosis. This review focuses on recent advances revealing fast and ultrafast clathrin-independent endocytosis occurring upon activation of discrete receptors and at synapses.

Section snippets

The need for fast endocytosis

Clathrin-mediated endocytosis is the dominant endocytic route to support housekeeping functions in cells (Figure 1a) [8, 16•]. However, some physiological processes require very rapid and scalable cellular response and need to be swiftly controlled to prevent exhaustion of the response. These processes include reaction to stress hormones (‘fight-or-flight’ reaction), membrane flux during directed cell migration (chemotaxis) or compensatory endocytosis following exocytosis of synaptic vesicles

Molecular mechanisms of fast endocytosis

There are several fast endocytic processes identified so far: macropinocytosis, activity-dependent bulk endocytosis (ADBE), fast-endophilin-mediated endocytosis (FEME), kiss-and-run and ultrafast endocytosis at synapses (Figure 1, Figure 2). All are clathrin-independent and are not constitutively active and may use different molecular mechanisms to rapidly remove receptors from the cell surface.

Why was fast endocytosis missed?

Whilst macropinocytosis has been known for decades (but perhaps not recognized as a fast endocytic pathway), FEME, ABDE, and ultrafast endocytosis have been only recently identified. Why were they not discovered sooner? The first obvious reason is their speed: ultrafast endocytosis is an order of magnitude faster than typical membrane dynamics captured by conventional recording systems. In the case of FEME, the budding events are slower compared to ultrafast endocytosis but only few (10–50)

Conclusions

Fast endocytosis serves specialized and transient tasks and does not seem to have housekeeping functions in cells. It is likely that the immediate role for ABDE and ultrafast endocytosis is not to restore synaptic vesicle pools but to clear fusion site for other vesicles to come in and fuse in rapid succession. In contrast, FEME appears to be more geared toward controlling the signaling of specific receptors.

Two main mechanisms appear to explain the speed of the pathways: (1) indiscriminate

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

E.B. is a Lister Institute Research Prize Fellow. S.W. is supported by Johns Hopkins University start-up fund and discovery award.

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