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Review
. 2009 Apr;109(4):1575-86.
doi: 10.1021/cr800473s.

Membrane protein targeting to the MVB/lysosome

Brian A Davies  1 , Jacqueline R E Lee, Andrea J Oestreich, David J Katzmann
Affiliations
Review

Membrane protein targeting to the MVB/lysosome

Brian A Davies et al. Chem Rev. 2009 Apr.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Roles for cellular machinery in MVB sorting and viral particle formation
Ubiquitin ligases, ESCRTs and associated factors (such as Alix, shown, or Vps4/SKD1, not shown) have been demonstrated to execute critical functions during MVB sorting (below) and viral budding (above). Vesicle formation is topologically similar in both cases as deformation is away from the cytoplasm. Viral budding can occur from the cell surface or into an intracellular compartment but only the former is presented for simplicity. In both contexts ubiquitin ligases can play a critical role in cargo selection through covalent modification of cargoes as well as an adaptor role independent of cargo ubiquitination. The role of Alix/Bro1 in MVB sorting is less clear than in viral budding, where it appears to play a role in cargo selection via bridging late domains with the ESCRTs (in which ESCRT-I and -II may be bypassed). “EI,” ESCRT-I; “E-II,” ESCRT-II; “EIII,” ESCRT-III; “Ligase,” ubiquitin ligases involved in these sorting events; “Ub,” ubiquitin; Purple ovals represent viral structural protein (e.g. Gag); Red ovals with stalk represent MVB cargo protein.
Figure 2
Figure 2. Potential roles for ubiquitin ligase function during MVB cargo selection
In this model, cargo selection is considered as both MVB sorting and viral budding. Membrane association of ligase may be facilitated by lipid binding domains such as the C2 domain found in Nedd4 homologs. Membrane-association may also be impacted by membrane adaptors (represented by the black PPXY-containing membrane protein), which may also impact cargo ubiquitination. Ligase recruitment to cargo may also occur via WW-PPXY interactions, which may additionally impact cargo or machinery ubiquitination during MVB sorting. These roles for ligases during cargo selection are not mutually exclusive. For example, machinery ubiquitination may be required to facilitate MVB sorting regardless of cargo ubiquitination status.
Figure 3
Figure 3. Model for membrane-associated ESCRT-I, ESCRT-II and cargo
Schematic representation of the ESCRT-I heterotetramer partial structure highlighting the elongated “stalk” region that separates the UEV domain of Vps23 from the “headpiece” region (from which Vps28 contacts ESCRT-II). ESCRT-I interactions with the membrane (via Vps37) and Vps27/Hse1 (via Vps23) have not been highlighted for simplicity. Ubiquitinated cargo is represented by the blue oval with the stalk and red “Ub.”
Figure 4
Figure 4. Interactions between Vps4, Vta1 and ESCRT-III
Six ESCRT-III proteins are present in yeast and share a conserved 5 helix core structure. The carboxyl-termini are more divergent and are implicated in coordinating ESCRT-III interactions with additional components of the MVB sorting machinery, including the AAA+ ATPase Vps4 (orange) and the Vps4 activator Vta1 (red) as well as Bro1/Alix and Ist1 (not shown). Vps4 contains an AAA+ domain involved in ATP hydrolysis, an insert within the AAA+ domain (β domain), and an amino-terminal MIT domain. Vta1 contains two MIT-related domains (MIT1, 2) and a carboxyl-terminal VSL region that binds the Vps4 β domain to stimulate Vps4 ATPase activity. The MIM1 domains present in Vps2 and Did2 interact with the Vps4 MIT domain and can stimulate Vps4 ATPase activity (MIM1*: an incomplete or divergent MIM1 is present in Vps24 and may mediate MIT interaction in some contexts). The MIM2 domain in Vps20 can also interact with the Vps4 MIT domain, but this interaction is distinct from the MIT-MIM1 interaction and does not stimulate Vps4 ATPase activity. Did2 also interacts with Ist1 and Vta1, with the Vta1 interaction motif apparently overlapping with MIM1. Vps60 interacts with Vta1 via the α4-α5 region, and interaction of Did2 or Vps60 with the Vta1 MIT2 domain stimulates ATPase activity of the Vta1-Vps4 complex. [Red arrows indicate interactions that stimulate Vta1-Vps4 ATPase activity.]
Figure 5
Figure 5. ESCRT-III assembly and disassembly
Yeast ESCRT-III appears to dynamically assemble and disassemble during MVB sorting. Functional analyses have suggested that sub-complexes exist within ESCRT-III. Vps20 and Snf7 appear to be the first sub-complex recruited, in part through ESCRT-II association with Vps20. Vps2 and Vps24 are then recruited in a Vps20- and Snf7-dependent manner. These four subunits comprise the core of ESCRT-III and can execute basal MVB sorting. Efficient MVB sorting also requires the accessory ESCRT-III subunits Did2 and Vps60. Did2 recruitment is dependent on Vps24 and Vps2, while Vps60 appears to be the last subunit recruited. While a layered organization is presented to illustrate this sequential recruitment, ESCRT-III appears instead to polymerize into fibrils to facilitate membrane deformation. Electron microscopy reconstructions of Vps24 homo-oligomers (inset left) or hetero-oligomers of truncated CHMP2/Vps2 and CHMP3/Vps24 (inset right) have identified two distinct assemblies of ESCRT-III that may be pertinent to membrane deformation. Disassembly of ESCRT-III is mediated by the Vta1-Vps4 complex. Interaction of the Vps20 MIM2 with the Vps4 MIT domain as well as association between Vps4 and the Did2-assocatiated factor Ist1 (not shown) have been implicated in facilitating Vta1-Vps4 recruitment. Interactions between Vps4 and MIM1 elements in Vps2 and Did2 as well as between Vta1 and Did2 or Vps60 then potentiate Vta1-Vps4 ATPase activity to stimulate ESCRT-III disassembly.
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