EsCrT protein complexes Mediate the formation of Intralumenal vesicles in Multivesicular bodies
As endosomes mature, patches of their membrane invaginate into the endosome lumen and pinch off to form intralumenal vesicles. Because of their appearance in the electron microscope such maturing endosomes are also called multivesicular bodies (Figure 13–54).
The multivesicular bodies carry endocytosed membrane proteins that are to be degraded. As part of the protein-sorting process, receptors destined for degradation, such as the occupied EGF receptors described previously, selectively partition into the invaginating membrane of the multivesicular bodies. In this way, both the receptors and any signaling proteins strongly bound to them are sequestered away from the cytosol where they might otherwise continue signaling. They also are made fully accessible to the digestive enzymes that eventually will degrade them (Figure 13–55). In addition to endocytosed membrane proteins, multivesicular bodies include the soluble content of early endosomes destined for late endosomes and digestion in lysosomes.
As discussed earlier, sorting into intralumenal vesicles requires one or multiple ubiquitin tags, which are added to the cytosolic domains of membrane proteins. These tags initially help guide the proteins into clathrin-coated vesicles in the plasma membrane. Once delivered to the endosomal membrane, the ubiquitin tags are recognized again, this time by a series of cytosolic ESCRT protein 0.5 µm
Figure 13–54 Electron micrograph of a multivesicular body. The large amount of internal membrane will be delivered to the lysosome, for digestion. (courtesy of andrew staehelin, from a. driouich, a. Jauneau and l.a. staehelin; Plant Physiol. 113:487–492, 1997. with permission from the american society of plant biologists.) complexes, (ESCRT-0, -I, -II, and -III), which bind sequentially and ultimately mediate the sorting process into the intralumenal vesicles. Membrane invagination into multivesicular bodies also depends on a lipid kinase that phosphorylates phosphatidylinositol to produce PI(3)P, which serves as an additional docking site for the ESCRT complexes; these complexes require both PI(3)P and the presence of ubiquitylated cargo proteins to bind to the endosomal membrane. ESCRT-III forms large multimeric assemblies on the membrane that bend the membrane (Figure 13–56).
Mutant cells compromised in ESCRT function display signaling defects. In such cells, activated receptors cannot be down-regulated by endocytosis and packaging into multivesicular bodies. The still-active receptors therefore mediate prolonged signaling, which can lead to uncontrolled cell proliferation and cancer.
Processes that shape membranes often use similar machinery. Because of strong similarities in their protein sequences, researchers think that ESCRT complexes are evolutionarily related to components that mediate cell-membrane deformation in cytokinesis in archaea. Similarly, the ESCRT machinery that drives the internal budding from the endosome membrane to form intralumenal vesicles is also used in animal cell cytokinesis and virus budding, which are topologically equivalent, as both processes involve budding away from the cytosolic surface of the membrane (Figure 13–57).
The fates of endocytosed receptors—and of any ligands remaining bound to them—vary according to the specific type of receptor. As we discussed, most receptors are recycled and returned to the same plasma membrane domain from which they came; some proceed to a different domain of the plasma membrane, thereby mediating transcytosis; and some progress to lysosomes, where they are degraded.