Trends in Biochemical Sciences
ReviewCellular Functions and Molecular Mechanisms of the ESCRT Membrane-Scission Machinery
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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