Selective trafficking of membrane proteins to lysosomes for destruction is required for proper cell signalling and metabolism. Ubiquitylation aids this process by specifying which proteins should be transported to the lysosome lumen by the multivesicular endosome pathway. The endosomal sorting complex required for transport (ESCRT) machinery sorts cargo labelled with ubiquitin into invaginations of endosome membranes. Then, through a highly conserved mechanism also used in cytokinesis and viral budding, it mediates the breaking off of the cargo-containing intraluminal vesicles from the perimeter membrane. The involvement of the ESCRT machinery in suppressing diseases such as cancer, neurodegeneration and infections underscores its importance to the cell.
Your institute does not have access to this article
Open Access articles citing this article.
Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Nature Communications Open Access 06 April 2022
Nature Communications Open Access 15 November 2021
Acta Neuropathologica Communications Open Access 28 September 2021
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gruenberg, J. & Stenmark, H. The biogenesis of multivesicular endosomes. Nature Rev. Mol. Cell Biol. 5, 317–323 (2004).
Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).
d'Azzo, A., Bongiovanni, A. & Nastasi, T. E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation. Traffic 6, 429–441 (2005).
Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell Dev. Biol. 19, 141–172 (2003).
Hicke, L. & Riezman, H. Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84, 277–287 (1996).
Galan, J. M., Moreau, V., Andre, B., Volland, C. & Haguenauer-Tsapis, R. Ubiquitination mediated by the Npi1p/Rsp5p ubiquitin-protein ligase is required for endocytosis of the yeast uracil permease. J. Biol. Chem. 271, 10946–10952 (1996).
Babst, M., Katzmann, D. J., Snyder, W. B., Wendland, B. & Emr, S. D. Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev. Cell 3, 283–289 (2002). This paper describes the first biochemical and functional characterization of ESCRT-II.
Babst, M., Katzmann, D. J., Estepa-Sabal, E. J., Meerloo, T. & Emr, S. D. Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev. Cell 3, 271–282 (2002). This is the first biochemical and functional characterization of ESCRT-III, and identification of Vps20–Vps32 and Vps24–Vps2 as subcomplexes of ESCRT-III.
Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106, 145–155 (2001). This paper coins the ESCRT name and provides the concept of an endosomal machinery that sorts ubiquitylated cargo into MVEs. It describes the first biochemical and functional characterization of ESCRT-I.
Bache, K. G., Brech, A., Mehlum, A. & Stenmark, H. Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J. Cell Biol. 162, 435–442 (2003).
Katzmann, D. J., Stefan, C. J., Babst, M. & Emr, S. D. Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J. Cell Biol. 162, 413–423 (2003).
Lu, Q., Hope, L. W., Brasch, M., Reinhard, C. & Cohen, S. N. TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Proc. Natl Acad. Sci. USA 100, 7626–7631 (2003).
Hurley, J. H. ESCRT complexes and the biogenesis of multivesicular bodies. Curr. Opin. Cell Biol. 20, 4–11 (2008).
Williams, R. L. & Urbe, S. The emerging shape of the ESCRT machinery. Nature Rev. Mol. Cell Biol. 8, 355–368 (2007).
Prag, G. et al. The Vps27/Hse1 complex is a GAT domain-based scaffold for ubiquitin-dependent sorting. Dev. Cell 12, 973–986 (2007).
Hofmann, K. & Falquet, L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem. Sci. 26, 347–350 (2001).
Raiborg, C., Bache, K. G., Mehlum, A., Stang, E. & Stenmark, H. Hrs recruits clathrin to early endosomes. EMBO J. 20, 5008–5021 (2001).
McCullough, J. et al. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr. Biol. 16, 160–165 (2006).
Gaullier, J.-M. et al. FYVE fingers bind PtdIns(3)P. Nature 394, 432–433 (1998).
Burd, C. G. & Emr, S. D. Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domain. Mol. Cell 2, 157–162 (1998).
Raiborg, C. et al. FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes. J. Cell Sci. 114, 2255–2263 (2001).
Roxrud, I., Raiborg, C., Pedersen, N. M., Stang, E. & Stenmark, H. An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor. J. Cell Biol. 180, 1205–1218 (2008).
Leung, K. F., Dacks, J. B. & Field, M. C. Evolution of the multivesicular body ESCRT machinery; retention across the eukaryotic lineage. Traffic 9, 1698–1716 (2008).
Puertollano, R. & Bonifacino, J. S. Interactions of GGA3 with the ubiquitin sorting machinery. Nature Cell Biol. 6, 244–251 (2004).
Puertollano, R. Interactions of TOM1L1 with the multivesicular body sorting machinery. J. Biol. Chem. 280, 9258–9264 (2005).
Seet, L. F., Liu, N., Hanson, B. J. & Hong, W. Endofin recruits TOM1 to endosomes. J. Biol. Chem. 279, 4670–4679 (2004).
Stuchell, M.D. et al. The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding. J. Biol. Chem. 279, 36059–36071 (2004).
Kostelansky, M. S. et al. Molecular architecture and functional model of the complete yeast ESCRT-I heterotetramer. Cell 129, 485–498 (2007). By combining data from several crystallographic studies, this paper describes a model of almost the whole ESCRT-I from yeast.
Morita, E. et al. Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding. Cell Host Microbe 2, 41–53 (2007).
Chu, T., Sun, J., Saksena, S. & Emr, S. D. New component of ESCRT-I regulates endosomal sorting complex assembly. J. Cell Biol. 175, 815–823 (2006).
Im, Y. J. & Hurley, J. H. Integrated structural model and membrane targeting mechanism of the human ESCRT-II complex. Dev. Cell 14, 902–913 (2008).
Hierro, A. et al. Structure of the ESCRT-II endosomal trafficking complex. Nature 431, 221–225 (2004). This is the first determination of the core of yeast ESCRT-II, showing that the core consists of eight winged-helix domains and that ESCRT-II consists of one Vps22, one Vps36 and two copies of Vps25.
Teo, H., Perisic, O., Gonzalez, B. & Williams, R. L. ESCRT-II, an endosome-associated complex required for protein sorting: crystal structure and interactions with ESCRT-III and membranes. Dev. Cell 7, 559–569 (2004).
Slagsvold, T. et al. Eap45 in mammalian ESCRT-II binds ubiquitin via a phosphoinositide-interacting GLUE domain. J. Biol. Chem. 280, 19600–19606 (2005).
Hirano, S. et al. Structural basis of ubiquitin recognition by mammalian Eap45 GLUE domain. Nature Struct. Mol. Biol. 13, 1031–1032 (2006).
Alam, S. L. et al. Structural basis for ubiquitin recognition by the human ESCRT-II EAP45 GLUE domain. Nature Struct. Mol. Biol. 13, 1029–1030 (2006).
Teo, H. et al. ESCRT-I core and ESCRT-II GLUE domain structures reveal central role for GLUE domain in linking to ESCRT-I and membranes. Cell 125, 99–111 (2006). This paper shows that the GLUE domain of yeast Vps36 binds Vps28 in ESCRT-I and ubiquitin via yeast-specific NZF zinc fingers, and that another face of the GLUE domain binds the endosomal lipid PtdIns(3)P.
Lata, S. et al. Structural basis for autoinhibition of ESCRT-III CHMP3. J. Mol. Biol. 378, 816–825 (2008).
Teis, D., Saksena, S. & Emr, S. D. Ordered assembly of the ESCRT-III complex on endosomes is required to sequester cargo during MVB formation. Dev. Cell 15, 578–589 (2008). On the basis of biochemical studies of intact yeast cells, this paper provides a model for the ordered assembly of ESCRT-III on membranes.
Saksena, S., Wahlman, J., Teis, D., Johnson, A. E. & Emr, S. D. Functional reconstitution of ESCRT-III assembly and disassembly. Cell 136, 97–109 (2009).
Rue, S. M., Mattei, S., Saksena, S. & Emr, S. D. Novel Ist1–Did2 complex functions at a late step in multivesicular body sorting. Mol. Biol. Cell 19, 475–484 (2008).
Raiborg, C. et al. Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nature Cell Biol. 4, 394–398 (2002). This paper shows that Hrs functions in degradative endosomal sorting of ubiquitylated membrane proteins, and that ESCRT-0 is concentrated in restricted microdomains of the endosome membrane.
Hirano, S. et al. Double-sided ubiquitin binding of Hrs-UIM in endosomal protein sorting. Nature Struct. Mol. Biol. 13, 272–277 (2006).
Fisher, R. D. et al. Structure and ubiquitin binding of the ubiquitin-interacting motif. J. Biol. Chem. 278, 28976–28984 (2003).
Haglund, K. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nature Cell Biol. 5, 461–466 (2003).
Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S. & Sorkin, A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21, 737–748 (2006).
Umebayashi, K., Stenmark, H. & Yoshimori, T. Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Mol. Biol. Cell 19, 3454–3462 (2008).
Bilodeau, P. S., Urbanowski, J. L., Winistorfer, S. C. & Piper, R. C. The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting. Nature Cell Biol. 4, 534–539 (2002).
Raiborg, C., Wesche, J., Malerød, L. & Stenmark, H. Flat clathrin coats on endosomes mediate degradative protein sorting by scaffolding Hrs in dynamic microdomains. J. Cell Sci. 119, 2414–2424 (2006).
Sachse, M., Urbe, S., Oorschot, V., Strous, G. J. & Klumperman, J. Bilayered clathrin coats on endosomal vacuoles are involved in protein sorting toward lysosomes. Mol. Biol. Cell 13, 1313–1328 (2002).
Komada, M. & Kitamura, N. Growth factor-induced tyrosine phosphorylation of Hrs, a novel 115-kilodalton protein with a structurally conserved putative zinc finger domain. Mol. Cell. Biol. 15, 6213–6221 (1995).
Takeshita, T. et al. Cloning of a novel signal-transducing adaptor molecule containing an SH3 domain and ITAM. Biochem. Biophys. Res. Commun. 225, 1035–1039 (1996).
Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).
Hoeller, D. et al. Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biol. 8, 163–169 (2006).
Kim, B. Y., Olzmann, J. A., Barsh, G. S., Chin, L. S. & Li, L. Spongiform neurodegeneration-associated E3 ligase mahogunin ubiquitylates TSG101 and regulates endosomal trafficking. Mol. Biol. Cell 18, 1129–1142 (2007).
Doyotte, A., Russell, M. R., Hopkins, C. R. & Woodman, P. G. Depletion of TSG101 forms a mammalian “Class E” compartment: a multicisternal early endosome with multiple sorting defects. J. Cell Sci. 118, 3003–3017 (2005).
Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).
Hanson, P. I., Roth, R., Lin, Y. & Heuser, J. E. Plasma membrane deformation by circular arrays of ESCRT-III protein filaments. J. Cell Biol. 180, 389–402 (2008). By using deep-etch electron microscopy of the plasma membrane of cells overexpressing ESCRT subunits, this paper provides spectacular images suggesting that membrane deformation is driven by circular arrays of Vps32 multimers.
Lata, S. et al. Helical structures of ESCRT-III are disassembled by VPS4. Science 321, 1354–1357 (2008).
Ghazi-Tabatabai, S. et al. Structure and disassembly of filaments formed by the ESCRT-III subunit Vps24. Structure 16, 1345–1356 (2008).
Pons, V. et al. Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies. PLoS Biol. 6, e214 (2008).
Obita, T. et al. Structural basis for selective recognition of ESCRT-III by the AAA ATPase Vps4. Nature 449, 735–739 (2007).
Samson, R. Y., Obita, T., Freund, S. M., Williams, R. L. & Bell, S. D. A role for the ESCRT system in cell division in Archaea. Science 322, 1710–1713, (2008). This paper shows that ESCRT-III and Vps4 function in cell division in the archaebacterium Sulfolobus acidocaldarius.
Spitzer, C. et al. The Arabidopsis elch mutant reveals functions of an ESCRT component in cytokinesis. Development 133, 4679–4689 (2006). This is the first demonstration that ESCRT proteins are involved in cytokinesis.
Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007). This paper provides the first demonstration that ESCRT proteins are involved in mammalian cytokinesis and identifies CEP55 as a key recruiter of ESCRTs to the midbody.
Morita, E. et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 26, 4215–4227 (2007).
Pineda-Molina, E. et al. The crystal structure of the C-terminal domain of Vps28 reveals a conserved surface required for Vps20 recruitment. Traffic 7, 1007–1016 (2006).
Martin-Serrano, J. The role of ubiquitin in retroviral egress. Traffic 8, 1297–1303 (2007).
Morita, E. & Sundquist, W. I. Retrovirus budding. Annu. Rev. Cell Dev. Biol. 20, 395–425 (2004).
Langelier, C. et al. Human ESCRT-II complex and its role in human immunodeficiency virus type 1 release. J. Virol. 80, 9465–9480 (2006).
Bowers, K. et al. Degradation of endocytosed epidermal growth factor and virally-ubiquitinated MHC class I is independent of mammalian ESCRTII. J. Biol. Chem. 81, 5094–5105 (2005).
von Schwedler, U. K. et al. The protein network of HIV budding. Cell 114, 701–713 (2003).
McCullough, J., Fisher, R. D., Whitby, F. G., Sundquist, W. I. & Hill, C. P. ALIX–CHMP4 interactions in the human ESCRT pathway. Proc. Natl Acad. Sci. USA 105, 7687–7691 (2008).
Amerik, A. Y., Nowak, J., Swaminathan, S. & Hochstrasser, M. The Doa4 deubiquitinating enzyme is functionally linked to the vacuolar protein-sorting and endocytic pathways. Mol. Biol. Cell 11, 3365–3380 (2000).
Swaminathan, S., Amerik, A. Y. & Hochstrasser, M. The Doa4 deubiquitinating enzyme is required for ubiquitin homeostasis in yeast. Mol. Biol. Cell 10, 2583–2594 (1999).
Nikko, E. & Andre, B. Evidence for a direct role of the Doa4 deubiquitinating enzyme in protein sorting into the MVB pathway. Traffic 8, 566–581 (2007).
Row, P. E., Prior, I. A., McCullough, J., Clague, M. J. & Urbe, S. The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. J. Biol. Chem. 281, 12618–12624 (2006).
Mizuno, E., Kobayashi, K., Yamamoto, A., Kitamura, N. & Komada, M. A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Traffic 7, 1017–1031 (2006).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).
Nixon, R. A. & Cataldo, A. M. Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J. Alzheimers Dis. 9, 277–289 (2006).
Bjørkøy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).
Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500 (2007).
Rusten, T. E., Filimonenko, M., Rodahl, L. M., Stenmark, H. & Simonsen, A. ESCRTing autophagic clearance of aggregating proteins. Autophagy 4, 233–236 (2008).
Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G. & Gao, F. B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567 (2007).
Kim, B. Y. & Akazawa, C. Endosomal trafficking of EGFR regulated by hVps18 via interaction of MVB sorting machinery. Biochem. Biophys. Res. Commun. Advance online publication doi:10.1016/j.bbrc.2007.08.046 (2007).
Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).
Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nature Genet. 37, 806–808 (2005).
Li, L. & Cohen, S. N. Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell 85, 319–329 (1996).
Xu, Z., Liang, L., Wang, H., Li, T. & Zhao, M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem. Biophys. Res. Commun. 311, 1057–1066 (2003).
Li, J., Belogortseva, N., Porter, D. & Park, M. Chmp1A functions as a novel tumor suppressor gene in human embryonic kidney and ductal pancreatic tumor cells. Cell Cycle 7, 2886–2893 (2008).
Krempler, A., Henry, M. D., Triplett, A. A. & Wagner, K. U. Targeted deletion of the Tsg101 gene results in cell cycle arrest at G1/S and p53-independent cell death. J. Biol. Chem. 277, 43216–43223 (2002).
Vaccari, T. & Bilder, D. The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating Notch trafficking. Dev. Cell 9, 687–698 (2005).
Thompson, B. J. et al. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila . Dev. Cell 9, 711–720 (2005).
Moberg, K. H., Schelble, S., Burdick, S. K. & Hariharan, I. K. Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell 9, 699–710 (2005).
Philips, J. A., Porto, M. C., Wang, H., Rubin, E. J. & Perrimon, N. ESCRT factors restrict mycobacterial growth. Proc. Natl Acad. Sci. USA 105, 3070–3075 (2008).
Vieira, O. V. et al. Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria. Mol. Cell. Biol. 24, 4593–4604 (2004).
Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).
Wollert, T., Wunder, C., Lippincott-Schwartz, J. & Hurley, J. H. Membrane scission by the ESCRT-III complex. Nature 458, 159–160 (2009)
C.R. is a postdoctoral fellow of the Norwegian Cancer Society. We also thank the Research Council of Norway, the Novo-Nordisk Foundation and the Hartmann Family Foundation for supporting our research.
The authors declare no competing financial interests.
Reprints and permissions information is available at http://www.nature.com/reprints.
Correspondence should be addressed to H.S. (email@example.com).
About this article
Cite this article
Raiborg, C., Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009). https://doi.org/10.1038/nature07961
Nature Reviews Drug Discovery (2022)
Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Nature Communications (2022)
Pharmaceutical Research (2022)
Science China Life Sciences (2022)
Unexpected organellar locations of ESCRT machinery in Giardia intestinalis and complex evolutionary dynamics spanning the transition to parasitism in the lineage Fornicata
BMC Biology (2021)