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The many functions of ESCRTs

Nature Reviews Molecular Cell Biology volume 21, pages 25–42 (2020)Cite this article

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Abstract

Cellular membranes can form two principally different involutions, which either exclude or contain cytosol. The ‘classical’ budding reactions, such as those occurring during endocytosis or formation of exocytic vesicles, involve proteins that assemble on the cytosol-excluding face of the bud neck. Inverse membrane involution occurs in a wide range of cellular processes, supporting cytokinesis, endosome maturation, autophagy, membrane repair and many other processes. Such inverse membrane remodelling is mediated by a heteromultimeric protein machinery known as endosomal sorting complex required for transport (ESCRT). ESCRT proteins assemble on the cytosolic (or nucleoplasmic) face of the neck of the forming involution and cooperate with the ATPase VPS4 to drive membrane scission or sealing. Here, we review similarities and differences of various ESCRT-dependent processes, with special emphasis on mechanisms of ESCRT recruitment.

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Fig. 1: Overview of ESCRT-mediated biological processes.
Fig. 2: Cytokinetic abscission and neuronal pruning.
Fig. 3: ESCRT recruitment and function in repair and budding of the plasma membrane.
Fig. 4: ESCRT recruitment and functions at the nuclear envelope.
Fig. 5: ESCRT recruitment and function at MVEs, phagophores and lysosomes.
Fig. 6: ESCRT-mediated viral budding and replication.

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Acknowledgements

The authors thank Camilla Raiborg and Eva M. Wenzel for critical reading of the manuscript. M.V. is a senior scientist and M.R. a postdoctoral fellow of the South-Eastern Norway Regional Health Authority (grant numbers 2018043 and 2016087, respectively). H.S. is supported by the Norwegian Cancer Society (grant no. 182698) and the Trond Paulsen InvaCell project (grant no. 35248). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262652.

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Author notes

  1. These authors contributed equally: Marina Vietri, Maja Radulovic.

Authors and Affiliations

  1. Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway

    Marina Vietri, Maja Radulovic & Harald Stenmark

  2. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway

    Marina Vietri, Maja Radulovic & Harald Stenmark

  3. Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Harald Stenmark

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  1. Marina Vietri
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Glossary

Midbody ring

Also called Flemming body. The central region of the intercellular bridge between dividing cells where plus-end anti-parallel central spindle microtubule bundles overlap and where several components crucial for cytokinesis and abscission are localized.

Chromosomal instability

An elevated frequency of chromosome segregation errors during cell division.

Centralspindlin

A heterotetrameric motor protein complex consisting of MKLP1–RACGAP1 dimers that is a key component of the midbody ring, where it bundles spindle microtubules and tethers the spindle apparatus to the cell cortex, thus stabilizing the intercellular bridge.

Septin

Septins are highly conserved GTP-binding proteins that assemble as monomers into hetero-oligomeric complexes and higher-order structures, including filaments and rings, that can associate with membranes and the cytoskeleton.

Cell cortex

Actin-rich network that is attached to the inner face of the plasma membrane and regulates cell shape.

Spastin

MIT domain-containing ATPase that utilizes ATP hydrolysis to sever microtubules.

Cdv fission machinery

Archaeal membrane fission machinery involved in cell division, virus budding and microvesicle secretion, with subunits sharing homology with ESCRT-III proteins and VPS4.

Lagging chromosomes

Single chromosomes that lag between the two nascent daughter nuclei of dividing cells, often arising when a single kinetochore is attached to both spindle poles during metaphase.

Aurora B

A serine/threonine-protein kinase that is the enzymatic subunit of the chromosome passenger complex.

Chromosome passenger complex

(CPC). Protein complex that surveys fidelity of genome segregation throughout the cell cycle. It consists of Aurora B kinase, Borealin, survivin and INCENP.

Abscission/NoCut checkpoint regulator

(ANCHR). Protein that participates in Aurora B-mediated regulation of the abscission checkpoint through retaining VPS4 at the midbody ring and thereby delaying abscission.

Unc51-like kinase 3

(ULK3). A serine/threonine-protein kinase with tandem MIT domains that allow it to bind and phosphorylate MIM-containing ESCRT-III proteins.

Dendritic arborization neurons

Nerve cells with highly branched dendrites.

Phosphatidylserine

A common phospholipid in cellular membranes, normally enriched on the cytosolic face.

Annexin A7

Member of the annexin protein family that consists of Ca2+-sensitive phospholipid-binding proteins that regulate various processes at endomembranes.

Necroptosis

A programmed form of caspase-independent, pro-inflammatory cell death that is activated downstream of death receptor signalling and mediated by RIPK1 and RIPK3 kinases.

MLKL

Mixed lineage kinase domain-like pseudokinase, a key effector of necroptotic cell death. Following activation by RIPK3 kinase, it oligomerizes and forms pores in the plasma membrane, permeabilizing the cell.

Pyroptosis

Pro-inflammatory programmed cell death induced by the activation of complexes known as inflammasomes, prominently by intracellular pathogens. It is executed by gasdermin D protein, which permeabilizes the plasma membrane.

Nuclear lamina

Protein network that provides rigidity and mechanical support to the nuclear envelope as well as functions in genome organization and regulation of transcription.

Lamins

Intermediate filament proteins expressed in most eukaryotes and that constitute the nuclear lamina.

Micronuclei

DNA structures, derived from chromosome segregation errors, that are not integrated within the cell nucleus but acquire a functional nuclear envelope after mitosis.

Barrier-to-autoantigen factor

(BAF). Adaptor protein that bridges DNA with the nuclear envelope via direct binding to DNA or chromatin-associated proteins as well as to LEM domain-containing proteins of the inner nuclear membrane.

LEM domain

A LAP2, emerin, MAN1 domain found in a subgroup of proteins that reside in the inner nuclear membrane or nucleoplasm.

MegaRNP

Large mRNA-containing ribonucleoprotein granules localized within the nucleoplasm of eukaryotic cells.

FYVE domain

An evolutionarily conserved protein domain that binds specifically to PtdIns3P.

Giant unilamellar vesicle

A vesicle of 1–100 μm diameter bounded by a single bilayer and containing an aqueous solution, used for biochemical and biophysical studies of membrane biology.

Actin-mediated endosomal recycling

Recycling of cargoes from endosomes to the plasma membrane, mediated by small actin-containing tubules that pinch off from endosomes.

Syntaxin 17

A protein encoded by the STX17 gene, recruited to autophagosomes where it forms a tight complex with a cytosolic protein, SNAP29, and a lysosomal protein, VAMP8, to mediate autophagosome–lysosome fusion.

Phagosomes

An intracellular compartment, derived from the plasma membrane and containing phagocytosed material.

Phagolysosomes

Fusion products between a phagosome and a lysosome.

Gag

A retroviral polyprotein processed during maturation into four separate proteins: matrix protein, capsid protein, nucleocapsid protein and p6, which together make the viral core.

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Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat Rev Mol Cell Biol 21, 25–42 (2020). https://doi.org/10.1038/s41580-019-0177-4

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