Review
Cellular Functions and Molecular Mechanisms of the ESCRT Membrane-Scission Machinery

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Trends

The ESCRT machinery is an evolutionarily conserved machinery for scission of membrane necks from their interior.

The ESCRT machinery is a modular system consisting of three subcomplexes named ESCRT-I, -II, and -III. The first two complexes function mainly in protein sorting and in recruitment of ESCRT-III, together with Bro1-domain containing proteins. By contrast, the ESCRT-III complex coordinates the membrane-severing function.

The ESCRT machinery is recruited to sites of action by subfunction-specific targeting modules. These factors include ESCRT-0 (MVE formation), CEP55 (cytokinesis), and Gag (virus budding), that are able to associate with ESCRT components and Bro1-domain proteins.

ESCRT-III subunits assemble into helical filaments that mediate membrane deformation and scission, in cooperation with the ATPase VPS4.

The endosomal sorting complex required for transport (ESCRT) machinery is an assembly of protein subcomplexes (ESCRT I-III) that cooperate with the ATPase VPS4 to mediate scission of membrane necks from the inside. The ESCRT machinery has evolved as a multipurpose toolbox for mediating receptor sorting, membrane remodeling, and membrane scission, with ESCRT-III as the major membrane-remodeling component. Cellular membrane scission processes mediated by ESCRT-III include biogenesis of multivesicular endosomes, budding of enveloped viruses, cytokinetic abscission, neuron pruning, plasma membrane wound repair, nuclear pore quality control, nuclear envelope reformation, and nuclear envelope repair. We describe here the involvement of the ESCRT machinery in these processes and review current models for how ESCRT-III-containing multimeric filaments serve to mediate membrane remodeling and scission.

Section snippets

The ESCRT Machinery: Conserved Membrane Scissors

Cellular membranes are highly-dynamic entities that undergo continuous remodeling, fusion, budding, and fission events. The best-characterized type of membrane fission involves budding towards the cytosol, such as endocytosis. This is mediated by cytosolic protein complexes that assemble around the neck of the forming vesicle or tubule. Mechanisms driving membrane budding and fission with the opposite topology, away from the cytosol into the extracellular or luminal space, are less well known.

ESCRT-Mediated Endosomal Sorting and Intraluminal Vesicle Formation

The endocytic pathway ensures cellular homeostasis and controls cell-to-cell communication in a healthy organism by regulation of nutrient uptake, signaling through growth factors and cytokines, and degradation of transmembrane proteins and misfolded proteins [19]. Upon endocytosis, transmembrane cargo is sorted into intraluminal vesicles (ILVs) of endosomes, generating multivesicular endosomes (MVEs). The MVEs then fuse with lysosomes and their content is degraded by lysosomal hydrolases.

Molecular Mechanisms of ESCRT-III Functions

Whereas much is known about the cell biological processes requiring the ESCRT machinery (Figure 1), our mechanistic understanding of how its subunits function in cells is poorly understood and largely relies on in vitro studies. The ESCRT-III components are small proteins (∼200 aa) sharing a core domain composed of a positively charged four-helical bundle. The two longest helices α1 and α2 are important for membrane binding and dimerization 24, 107, 108, and form a flexible helical hairpin [109]

Concluding Remarks and Future Perspectives

With the recent realization that ESCRT-mediated membrane deformation and scission are crucial for multiple cellular processes (Figure 1), it is evident that we need to learn more about how the ESCRT machinery functions (see Outstanding Questions). Largely thanks to yeast genetics, we currently have a relatively good inventory of the various ESCRT subunits and accessory proteins (Figure 3), but for most ESCRT-dependent processes we do not have a complete picture of how ESCRT components are

Acknowledgments

C.R. is a senior research fellow of the Norwegian Cancer Society. E.M.W. is a senior research fellow of the South-Eastern Norway Regional Health Authority. H.S. is supported by a grant from the Norwegian Cancer Society. This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project 179571.

Glossary

Compartment for unconventional protein secretion (CUPS)
in yeast, allows the secretion of proteins independently of the endoplasmic reticulum; consists of vesicles and tubules surrounded by a cup-shaped membrane.
Cytokinetic abscission
final step of cell division where the intercellular bridge connecting the two daughter cells is cleaved.
Ectosome
also known as a microvesicle, an extracellular vesicle derived by budding and shedding from the plasma membrane (PM) without endosomal involvement.
Exosome

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