ESCRT & Co

Abstract

Components of the ESCRT (endosomal sorting complex required for transport) machinery mediate endosomal sorting of ubiquitinated membrane proteins. They are key regulators of biological processes important for cell growth and survival, such as growth-factor-mediated signalling and cytokinesis. In addition, enveloped viruses, such as HIV-1, hijack and utilize the ESCRTs for budding during virus release and infection. Obviously, the ESCRT-facilitated pathways require tight regulation, which is partly mediated by a group of interacting proteins, for which our knowledge is growing. In this review we discuss the different ESCRT-modulating proteins and how they influence ESCRT-dependent processes, for example, by acting as positive or negative regulators or by providing temporal and spatial control. A number of the interactors influence the classical ESCRT-mediated process of endosomal cargo sorting, for example, by modulating the interaction between ubiquitinated cargo and the ESCRTs. Certain accessory proteins have been implicated in regulating the activity or steady-state expression levels of the ESCRT components, whereas other interactors control the cellular localization of the ESCRTs, for example, by inducing shuttling between cytosol and nucleus or endosomes. In conclusion, the discovery of novel interactors has and will extend our knowledge of the biological roles of ESCRTs.

Negative regulation of Drosophila JAK–STAT signalling by endocytic trafficking

“…Previous reports have shown that removal of tsg101 and components that mediate sorting of ubiquitylated transmembrane proteins to late endosomes (Roxrud et al, 2010) within the developing eye imaginal disc result in the activation of Notch pathway signalling and non-autonomous overgrowth of surrounding tissue (Moberg et al, 2005;Vaccari and Bilder, 2005). Strikingly, this non-autonomous overgrowth is mediated by the ectopic expression of Upd, which is a target gene of Notch in the developing eye (Chao et al, 2004;Flaherty et al, 2009).…”

Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles

“…ESCRTs consist of approximately twenty proteins that assemble into four complexes (ESCRT-0, -I, -II and -III) with associated proteins (VPS4, VTA1, ALIX), which are conserved from yeast to mammals (Henne et al, 2011;Roxrud et al, 2010). The ESCRT-0 complex recognizes and sequesters ubiquitylated proteins in the endosomal membrane, whereas the ESCRT-I and -II complexes appear to be responsible for membrane deformation into buds with sequestered cargo, and ESCRT-III components subsequently drive vesicle scission (Hurley and Hanson, 2010;Wollert et al, 2009).…”

The Roles of ESCRT Proteins in Healthy Cells and in Disease

“…The role of ESCRT-II in cytokinesis is unclear, although studies conducted by Langelier et al, 2006 indicate that Vps22 of ESCRT-II is located on the centrosomes and is involved in the maturation of these organelles. The mechanisms behind ESCRT mediated scission and their role in microtubule disassembly have been recently reviewed in detail by Henne et al, 2011 andRoxrud et al, 2010 and will not be further discussed in this review.…”

“…Given their importance in fundamental cellular processes, it is not surprising that ESCRT dysfunction is associated with numerous diseases, including neurodegenerative disorders, cancer and infectious diseases. The dynamics and regulation of the ESCRT machinery have been extensively reviewed (Hurley & Emr, 2006;Saksena et al, 2007;Williams & Urbe, 2007;Raiborg & Stanmark, 2009;Hanson et al, 2009;Roxrud et al, 2010;Henne et al, 2011) and will only be mentioned briefly here. This review focuses on understanding the role of the ESCRTs' in disease using model systems, to better understand the mechanisms behind their role in pathogenesis.…”

“…Ubiquitinated endosomal cargo targeted for lysosomal degradation is initially recognised by ESCRT-0. ESCRT-I, -II and -III which are subsequently recruited to the endosomal membrane by protein-protein interactions between the four complexes (reviewed by Roxrud et al, 2010). The ubiquitinated cargo is further concentrated on the endosomal membrane by the action of ESCRT-I and -II, furthermore invaginations that form from the endosomal membrane to become ILVs depend upon ESCRT-III and Vps4 -facilitated membrane abscission (Elia et al, 2011;Babst et al, 2011).…”