18.7:
Intralumenal Vesicles and Multivesicular Bodies
Multivesicular bodies or MVBs are specialized endosomes containing intraluminal vesicles or ILVs formed by inward budding of the endosomal membrane. This inward budding is coordinated by protein complexes called endosomal sorting complexes required for transport or ESCRTs.
Proteins destined for degradation or signaling proteins that are to be sequestered away from the cytosol are partitioned into these ILVs.
E3 ligases attach ubiquitin to these proteins at the plasma membrane, and the protein is internalized through receptor-mediated endocytosis. Then, the endocytic vesicle fuses with the early endosome.
Once the early endosome enters the process of maturation, four types of protein complexes, numbered ESCRT-0, I, II and III, act sequentially to recognize and sort the ubiquitin-tagged protein.
ESCRT-0 first recognizes the ubiquitinated protein on the endosomal membrane and ESCRT-I and II induce the inward budding of the membrane. ESCRT-II triggers the homo-oligomerization of ESCRT-III. The growing ESCRT-III oligomers also recruit enzymes that deubiquitinate the protein.
Then ESCRT III, along with an ATPase, Vps4, mediates the membrane fission and release of ILVs, transforming the endosome into an MVB.
18.7:
Intralumenal Vesicles and Multivesicular Bodies
Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the cell.
MVBs were first observed in neuronal cells in 1955 using electron microscopy. MVBs have a diameter of 400-500 nm, are spherical, and were initially thought to be a form of the late endosome; however, recent studies have shown that MVBs are an intermediate form of these organelles between the early and the late endosomes.
ILV formation takes place when a ubiquitin-tagged protein enters the cell in an endocytic vesicle and fuses with the early endosome. As the early endosome matures, the endosomal membrane bends inwards to form ILVs. An ESCRT protein complex mediates ILV formation. Phosphatidylinositol 3-phosphate (PtdIns3P) is also required for ILV formation. PtdIns3P acts as a docking site for ESCRTs for the bending of the endosomal membrane.
The ESCRT complex and the ATPase, Vps4, required for ILV formation can be hijacked by enveloped retroviruses that infect host cells. Normally, ILVs are formed inside maturing endosomes with the help of ESCRTs within the cell, and the ubiquitin-tagged proteins are recognized and sorted into ILVs. In contrast, retroviruses use the ESCRTs to be released outside the cell. For example, the human immunodeficiency virus (HIV) codes for proteins, such as Gag, NC-p2, and Tat, that require ubiquitination for export. This ubiquitination is essential because ESCRTs and Vps4 recognize and sort only ubiquitin-tagged proteins into viral buds. Once the viral particles bud off from an infected cell, they are released into the extracellular space to infect other host cells.
Suggested Reading
- Gruenberg, J., & Stenmark, H. (2004). The biogenesis of multivesicular endosomes. Nature reviews Molecular cell biology, 5(4), 317-323.
- Peng, X., Yang, L., Ma, Y., Li, Y., & Li, H. (2020). Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies. Cell Communication and Signaling, 18(1), 1-15.
- Stuchell, M.D., Garrus, J.E., Müller, B., Stray, K.M., Ghaffarian, S., McKinnon, R., Kräusslich, H.G., Morham, S.G. and Sundquist, W.I.. (2004). The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding. Journal of Biological Chemistry, 279(34),.36059-36071.