Key Points
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Endosomal sorting complex required for transport (ESCRT) proteins carry out scission of membrane necks with a topology (or sidedness) opposite to that of the better-understood process carried out by coat proteins, dynamin and BAR (Bin, amphiphysin and Rvs) domain proteins.
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ESCRT-mediated reverse-topology membrane scission is initiated by two upstream branches: the first comprising ESCRT-I and ESCRT-II, and the second comprising ALIX.
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The ESCRT-III protein family has 12 different subunits in humans. ESCRT-III monomers are about 200 amino acids in length and have open and closed conformations.
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ESCRT-III proteins can assemble into flat spirals, helical tubes or conical funnels.
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ESCRT-III assemblies are taken apart by the AAA+ ATPase vacuolar protein sorting-associated 4 (VPS4), which unfolds ESCRT-III monomers and threads them through a central pore of the VPS4 hexamer.
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It is currently unresolved whether scission is mediated by the drawing-together of membrane necks by a tapered dome, buckling by the mechanical spring-like action of curved ESCRT filaments or some other means.
Abstract
The narrow membrane necks formed during viral, exosomal and intra-endosomal budding from membranes, as well as during cytokinesis and related processes, have interiors that are contiguous with the cytosol. Severing these necks involves action from the opposite face of the membrane as occurs during the well-characterized formation of coated vesicles. This 'reverse' (or 'inverse')-topology membrane scission is carried out by the endosomal sorting complex required for transport (ESCRT) proteins, which form filaments, flat spirals, tubes and conical funnels that are thought to direct membrane remodelling and scission. Their assembly, and their disassembly by the ATPase vacuolar protein sorting-associated 4 (VPS4) have been intensively studied, but the mechanism of scission has been elusive. New insights from cryo-electron microscopy and various types of spectroscopy may finally be close to rectifying this situation.
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Acknowledgements
Research on endosomal sorting complexes required for transport (ESCRTs) in the Hurley laboratory is supported by the US National Institutes of Health, grant AI112442. J.H.I. is supported by the Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV (CHEETAH), US National Institutes of Health, grant GM082545.
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Supplementary information
Supplementary information S1 (table)
ESCRT subunit nomenclature (PDF 77 kb)
Supplementary information S2 (movie)
Animation of the dome model of ESCRT-mediated reverse-topology membrane scission. See legend to Fig. 7a for explanation of features. ESCRT-I (green), ESCRT-II (orange), ESCRT-III (yellow), ALIX (purple), VPS4 (pink), Gag (blue). (MOV 50707 kb)
Supplementary information S3 (movie)
Animation of the reverse dome model of ESCRT-mediated reverse-topology membrane scission. See Fig. 7b. ESCRT-I (green), ESCRT-II (orange), ESCRT-III (yellow), ALIX (purple), VPS4 (pink), Gag (blue). (MOV 51580 kb)
Supplementary information S4 (movie)
Animation of the buckling model of ESCRT-mediated reverse-topology membrane scission. See Fig. 7c. ESCRT-I (green), ESCRT-II (orange), ESCRT-III (yellow), ALIX (purple), VPS4 (pink), Gag (blue). (MOV 52453 kb)
Supplementary information S5 (movie)
Animation of the possible role of ESCRT proteins in endocytic cargo sorting. Cargo proteins (red) recruit ESCRT-I (green) and ESCRT-II (orange). ESCRT-III (yellow) is recruited by ESCRT-II and grows in concentric rings of increasing diameter, forming a flat disc. The addition of a second type of ESCRT-III protein (teal) causes buckling of the ESCRT-III disc, forming a cone. Depolymerization of second ESCRT-III rings by VPS4 (pink) allows ESCRT-III to return to a flattened disc morphology and for membrane fission to occur. (MOV 117858 kb)
Glossary
- Membrane necks
-
Narrow membranous connections linking two entities, including: nascent endosomes, exosomes, enveloped viruses and intraluminal vesicles to their membranes of origin; daughter cell to mother cell or another daughter cell; and the cytosol to the lumen of a double-membrane structure, such as the nucleus or a nascent autophagosome.
- Reverse-topology scission
-
The severing of membrane necks when the scission factors function from the membrane face contiguous with the interior of the neck.
- Multivesicular bodies
-
(MVBs). Late endosomes containing internal vesicles.
- Cytokinesis
-
The separation of daughter cells, which is the final stage in cell division, in which the membrane and microtubules connecting the two cells are severed.
- Ubiquitin
-
A 76-amino-acid protein whose covalent conjugation to target proteins can (among many other fates) mark them as substrates for the endosomal sorting complex required for transport (ESCRT) system.
- Giant unilamellar vesicles
-
Synthetic vesicles of ∼5–50 μm in diameter; a popular model system for in vitro studies of membrane remodelling.
- Nucleation
-
The kinetic step in which an initial seed unit is assembled that, when formed, can readily grow into a larger structure.
- Intercellular bridge
-
The narrow membranous and microtubule-containing structure connecting two daughter cells immediately before their separation in cytokinesis.
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Schöneberg, J., Lee, IH., Iwasa, J. et al. Reverse-topology membrane scission by the ESCRT proteins. Nat Rev Mol Cell Biol 18, 5–17 (2017). https://doi.org/10.1038/nrm.2016.121
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DOI: https://doi.org/10.1038/nrm.2016.121
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