Molecular Mechanism of Multivesicular Body Biogenesis by ESCRT Complexes

By T. Wollert, James H. Hurley. Nature, 2010

765 citations recorded by the source corpus.

When internalized receptors and other cargo are destined for lysosomal degradation, they are ubiquitinated and sorted by the endosomal sorting complex required for transport (ESCRT) complexes 0, I, II and III into multivesicular bodies. Multivesicular bodies are formed when cargo-rich patches of the limiting membrane of endosomes bud inwards by an unknown mechanism and are then cleaved to yield cargo-bearing intralumenal vesicles. The biogenesis of multivesicular bodies was reconstituted and visualized using giant unilamellar vesicles, fluorescent ESCRT-0, -I, -II and -III complexes, and a membrane-tethered fluorescent ubiquitin fusion as a model cargo. Here we show that ESCRT-0 forms domains of clustered cargo but does not deform membranes. ESCRT-I and ESCRT-II in combination deform the membrane into buds, in which cargo is confined. ESCRT-I and ESCRT-II localize to the bud necks, and recruit ESCRT-0-ubiquitin domains to the buds. ESCRT-III subunits localize to the bud neck and efficiently cleave the buds to form intralumenal vesicles. Intralumenal vesicles produced in this reaction contain the model cargo but are devoid of ESCRTs. The observations explain how the ESCRTs direct membrane budding and scission from the cytoplasmic side of the bud without being consumed in the reaction.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/5806822a1b2e84d207bc177204ffa8580e79968f

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Citations in the corpus

Exosomes as a new frontier of cancer liquid biopsy (2022, background): “The mechanisms of cargo sorting are still unclear, both endosomal sorting complex required for transport (ESCRT)-dependent manner [30, 31] and ESCRT-independent mechanism have been reported to participate in this process [32, 33].”
Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis (2019, background): “The regulation of MVB and exosome formation and release is through the endosomal sorting complexes required for transport (ESCRT) pathway [44,45].”
Wnt Signaling Requires the Sequestration of Glycogen Synthase Kinase 3 inside Multivesicular Endosomes (2010, neutral): “Wnt Signaling Requires the ESCRT Machinery The molecular machinery that forms endosomal intralumenal vesicles has been well characterized (Wollert and Hurley, 2010).”
Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake (2016, neutral): “Second, the endosomal sorting complexes required for transport (ESCRTs) are recruited to the site of ILV formation (Wollert and Hurley 2010; Colombo et al. 2013).”
Focus on Extracellular Vesicles: Introducing the Next Small Big Thing (2016, background): “Although a recent in vitro study involving giant unilammellar vesicles questioned this “lipid-only” hypothesis of ILV formation [60], since the authors found that no particular lipid magic bullet was required for ILV formation, several discrepancies between in vitro and in vivo observations preclude”
Effect of exosomal miRNA on cancer biology and clinical applications (2018, background): “Study of late endosome components, such as Alix, tumor susceptibility gene 101 (TSG101) and tetraspanins, promotesanunderstanding of exosomal origin [16].”
Syndecan–syntenin–ALIX regulates the biogenesis of exosomes (2012, background): “Note that truncated forms of Alix containing the V domain interact with the two parts of the N-Ter domain of syntenin that contain LYPXL motifs, (1-30) and (31-60), and that mutation of the three LYPXL motifs (YP to AA) abolishes the interaction.”
Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. (2011, background): “form buds of comparable sizes that are cleaved as intraluminal vesicles into the interior of the late endosome [16].”
Exosomes in Tumor Microenvironment Influence Cancer Progression and Metastasis (2013, background): “The ESCRT complex recognize ubiquinated membrane proteins and promote their internalization into the multivesicular endosome [9].”
Influenza Virus Assembly and Budding (2011, neutral): “…ESCRT-I and -II complexes are able to modify membrane curvature and provide a scaffold for the recruitment of cargo proteins; however, addition of the ESCRT-III complex is required to mediate membrane scission and the release of the budding vesicle (Wollert and Hurley, 2010; Wollert et al., 2009).”
Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies (2013, neutral): “There are four multi-protein complexes required for ILV formation and they are termed ESCRT 0, I, II, and III [39–41].”
The ESCRT pathway. (2011, background): “It is possible that ESCRT-III could coat the vesicle interior during vesicle maturation, but if so the ESCRTs are efficiently removed prior to scission because they are not consumed in the reaction (Babst, 2005; Wollert and Hurley, 2010).”