No strings attached: the ESCRT machinery in viral budding and cytokinesis

Abstract

Since the initial discovery of the endosomal sorting complex required for transport (ESCRT) pathway, research in this field has exploded. ESCRT proteins are part of the endosomal trafficking system and play a crucial role in the biogenesis of multivesicular bodies by functioning in the formation of vesicles that bud away from the cytoplasm. Subsequently, a surprising role for ESCRT proteins was defined in the budding step of some enveloped retroviruses, including HIV-1. ESCRT proteins are also employed in this outward budding process, which results in the resolution of a membranous tether between the host cell and the budding virus particle. Remarkably, it has recently been described that ESCRT proteins also have a role in the topologically equivalent process of cell division. In the same way that viral particles recruit the ESCRT proteins to the site of viral budding, ESCRT proteins are also recruited to the midbody - the site of release of daughter cell from mother cell during cytokinesis. In this Commentary, we describe recent advances in the understanding of ESCRT proteins and how they act to mediate these diverse processes.

Fig. 1.

A diagram illustrating topologically equivalent `budding' events for which the ESCRT machinery is required. The formation of intralumenal vesicles (ILVs) within multivesicular bodies (MVBs), viral budding and abscission during cytokinesis all require the resolution of a cytoplasm-filled membranous tether.

Fig. 2.

A model for ESCRT-III–VPS4-mediated membrane scission. Following recruitment by upstream ESCRT complexes, ESCRT-III assembles on the membrane. N-terminal basic domains (blue) of ESCRT-III subunits attach to the membrane, whereas the flexibly linked C-terminal MIMs (MIT-interaction motifs; red) project away from the membrane. The AAA-ATPase VPS4 assembles into a double-ring complex and interacts with ESCRT-III subunits via N-terminal MIT (microtubule interaction and trafficking) domains (yellow). The regulatory protein LIP5 (purple) forms a dimer and associates with the VPS4 complex (note that the MIT domains of LIP5 have been omitted for clarity). Narrowing of the membrane tube might be concurrent with VPS4-mediated disassembly of the ESCRT-III lattice. It is possible that subunit removal via mechanical extraction through the VPS4 complex could reduce the diameter of the tube and lead to constriction. Top two panels show vertical and horizontal cross-sections of a wide membrane tube. The bottom two panels illustrate cross-sections of the thinner tube formed following the removal of the ESCRT-III lattice from the wider tube.

Fig. 3.

A model for ESCRT-mediated abscission. Golgi- and endosome-derived vesicles are transported to the midbody along microtubules, a process that is regulated by Rab GTPases. Association with the exocyst-tethering complex at the midbody may constrain the site of vesicle fusion. The v-SNARE endobrevin (also known as VAMP8) and the plasma-membrane-associated t-SNARE syntaxin-2 mediate vesicle fusion with the plasma membrane. Cep55 recruits ALIX and Tsg101 to the midbody for subsequent ESCRT-III assembly. Tsg101 can interact with other proteins that are involved in cytokinesis – in particular CD2AP, ROCK1 and IQGAP. The coordinated recruitment of VPS4 and spastin, along with other regulatory proteins (hIST1 and CHMP1B), to the midbody may complete abscission by severing microtubules and mediating membrane fusion of the remaining tether via ESCRT-III disassembly (arrows).