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  • Review Article
  • Published:

The emerging shape of the ESCRT machinery

Nature Reviews Molecular Cell Biology volume 8, pages 355–368 (2007)Cite this article

Key Points

  • Central to the function of the MVB pathway for trafficking to lysosomes are the endosomal sorting complex required for transport-0 (ESCRT-0), -I, -II and –III complexes, which are represented in all eukaryotic taxa. Ubiquitylation is the best characterised signal for entry into this pathway, and all of the ESCRTs, except for ESCRT-III, recognize ubiquitin.

  • The ESCRT-0 complex recruits ubiquitylated cargo to flat clathrin-coated dynamic microdomains on endosomes and is essential to recruiting ESCRT-I. The endosomal recruitment of ESCRT-0 is mediated by binding to 3-phosphoinosides, which are enriched in early endosome membranes.

  • ESCRT-I is built around a heterotrimeric core to which flexibly connected modules that recognize ubiquitylated cargo and the downstream ESCRT-II complex are connected. This complex is essential for intralumenal vesicle formation and vacuolar stability.

  • The four-subunit ESCRT-II core complex is built from winged-helix domains. The subunits link directly to the downstream VPS20 subunit of ESCRT-III, whereas the N-terminal GLUE domain of VPS36 recognizes ubiquitin, 3-phosphoinositides and, in yeast, the upstream ESCRT-I.

  • ESCRT-III subunits are represented in all eukaryotic taxa. These subunits heterodimerize via a long N-terminal helical hairpin to form lattices on endosomal membranes that require the AAA+ ATPase VPS4 for subsequent disassembly. The lattice has been proposed to facilitate membrane curvature and the formation of intralumenal vesicles.

  • De-ubiquitinases are recruited by ESCRT-III and can remove ubiquitin from cargo before and after it is committed to entry into intralumenal vesicles.

Abstract

The past two years have seen an explosion in the structural understanding of the endosomal sorting complex required for transport (ESCRT) machinery that facilitates the trafficking of ubiquitylated proteins from endosomes to lysosomes via multivesicular bodies (MVBs). A common organization of all ESCRTs is a rigid core attached to flexibly connected modules that recognize other components of the MVB pathway. Several previously unsuspected key links between multiple ESCRT subunits, phospholipids and ubiquitin have now been elucidated, which, together with the detailed morphological analyses of ESCRT-depletion phenotypes, provide new insights into the mechanism of MVB biogenesis.

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Figure 1: A schematic of the ESCRT machinery involved in sorting cargo to lysosomes via MVBs.
Figure 2: The organization of ESCRT-0.
Figure 3: The architecture of the cores of ESCRT-I and ESCRT-II.
Figure 4: The architectures of ESCRT-III.

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Acknowledgements

We would like to thank M. West, G. Odorizzi, C. Futter, J.-H. Shim, M. Russell, C. Hopkins, P. Woodman, S. Stuffers, A. Brech, H. Stenmark and L. Pullan, all for providing high-resolution EM images that, regrettably, could not be included in the final manuscript owing to space limitations.

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  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Roger L. Williams

  2. Physiological Laboratory, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK

    Sylvie Urbé

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DATABASES

Protein Data Bank

1DVP

1M4P

1S1Q

1VFY

1W7P

1YXR

2CAY

2D3G

2F66

2GD5

2HTH

2J9U

FURTHER INFORMATION

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Sylvie Urbé's homepage

Glossary

Intralumenal vesicle

A small <50-nm vesicle that forms through inward budding of the endosomal membrane away from the cytosol.

Multivesicular body (MVB)

A morphologically defined endocytic organelle that is characterized by multiple internal vesicles in which internalized receptors are packaged before degradation.

Lysosome

Membrane-bound organelle in higher eukaryotic cells that has an acidic interior and is the major storage site of the degradative enzymes (acidic hydrolases) that are responsible for the breakdown of internalized proteins and many membrane proteins. Functionally equivalent to the yeast vacuole.

Ubiquitylation

Covalent attachment of ubiquitin via its C-terminal Gly to Lys side chains in target proteins. Ubiquitin can form seven distinct polyubiquitin chains through seven internal Lys residues.

Endosomal sorting complex required for transport

(ESCRT). A multimeric protein complex that was first identified biochemically in yeast. ESCRTs control the sorting of endosomal cargo proteins into internal vesicles of multivesicular bodies.

ESCRT-0

Nomenclature for the HRS–STAM complex, which was proposed as a recent extension of the originally defined ESCRT-I, -II and -III.

De-ubiquitylating enzyme

Protease that can cleave the isopeptide bond between ubiquitin and Lys side chains of ubiquitylated substrates.

Early endosome antigen-1

A protein that plays a part as a tether in the homotypic fusion of early endosomes.

Phosphatidylinositol-3-phosphate

(PtdIns3P). A phospholipid that is highly enriched in endosomal membranes. Several ESCRT proteins encode PtdIns3P-binding domains, which allow these proteins to be recruited to endosomes.

Clathrin

Coat protein that decorates clathrin-coated vesicles and is recruited by ESCRT-0 to sorting endosomes where it forms a flat double-layered coat, which is thought to sequester ubiquitylated cargo prior to incorporation into intralumenal vesicles.

Vacuolar hydrolases

Enzymes that are responsible for protein degradation in late endosomes and lysosomes.

Class E compartment

Aberrant multilamellar or multicisternal membrane-bound compartment in which both endocytic and biosynthetic proteins en route to the vacuole accumulate in Vps-mutant yeast of the class E subtype.

CHMP

A family of structurally related proteins with a basic N terminus and an acidic C terminus that interact with each other to form ESCRT-III. Some CHMPs have also been associated with nuclear functions.

MIT

A domain found in microtubule interacting and trafficking proteins that forms a three-helix bundle. Some MIT domains, including those of VPS4 and AMSH, bind to CHMPs.

AAA+ ATPases

ATPases associated with various cellular activities: a superfamily of structurally related proteins that control diverse functions, including protein disassembly.

Proteasome

Multi-enzyme complex responsible for the majority of protein turnover in eukaryotic cells that degrades proteins tagged with a particular type of ubiquitin chain.

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Williams, R., Urbé, S. The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol 8, 355–368 (2007). https://doi.org/10.1038/nrm2162

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