ESCRT proteins in the context of exosome/EV release

Extracellular vesicles

Explaining ESCRT (endosomal sorting complexes required for transport) proteins in the release of extracellular vesicles (EV).

The formation and release of exosomes/EVs rely on structures called endosomes that occur within certain cells. Within the endosomes, specific groups of proteins called ESCRT proteins function. ESCRT is important for controlling the processes of vesicle formation, selective sorting of proteins, and release of vesicles. Thus, ESCRT proteins play a key role in intercellular communication, and they can have significant effects on the physiological and pathological states of cells.

These proteins perform the necessary tasks to ensure that exosomes/EVs contain the appropriate components and are accurately transported from the endosomes to the extracellular space. This process consists of a series of molecular steps involving different ESCRT complexes (ESCRT-0, I, II, III) participating in the process.

  1. Selection of Ubiquitinated Proteins: As endosome maturation progresses, ubiquitinated proteins brought from various locations within the cell accumulate on the endosome membrane. Ubiquitination refers to a biochemical process in which a small protein called ubiquitin binds to a target protein. Ubiquitin is a 76-amino acid protein present in all eukaryotic cells. The process of ubiquitination occurs as follows: Activation: Ubiquitin-activating enzymes (E1) activate ubiquitin in the presence of ATP. Conjugation: Ubiquitin-conjugating enzymes (E2) receive activated ubiquitin. Ligation: Ubiquitin ligases (E3) receive ubiquitin from E2 and attach it to specific target proteins. Ubiquitinated proteins play a crucial role in the formation of intraluminal vesicles (ILVs). Intraluminal vesicles refer to small vesicular structures present within the endosomes. They are formed internally within the cellular endosome structure.
  2. Role of ESCRT-0: Here, the ESCRT-0 complex comes into play. ESCRT-0 specifically binds to ubiquitinated proteins and determines the site (domain) on the endosome membrane where vesicle formation begins.
  3. Initiation of Membrane Curvature: Through the action of ESCRT-0, the presence of accumulated ubiquitinated proteins in specific domains causes the endosome membrane to bend inward. This marks the initial stage of intraluminal vesicle formation.
  4. Action of ESCRT-I and ESCRT-II: Subsequently, the ESCRT-I and ESCRT-II complexes intervene, further deepening the curvature of the membrane and forming the “bud” of the vesicle protruding into the endosome lumen. These complexes deform the membrane further and facilitate vesicle formation.
  5. ESCRT-III Complex: Finally, ESCRT-III binds and assists in the complete formation and detachment of the mature vesicle. This complex bends and closes the membrane, fully separating the vesicle within the endosome lumen.

Therefore, ESCRT proteins are involved in all stages of the process of generating and releasing EVs from endosomes, enabling precise communication and substance transport within cells. Such processes are essential for cell survival, growth, and differentiation, and abnormalities in these processes can lead to pathological conditions.