ESCRT

Endosomal Sorting Complex Required for Transport (ESCRT) is a multi-subunit protein complex involved in various cellular processes, including the sorting of ubiquitinated membrane proteins into the lumen of multivesicular bodies (MVBs), viral budding, autophagy, and the final abscission step during cytokinesis. The ESCRT machinery is highly conserved across eukaryotes, highlighting its essential role in cell biology.

Function

The primary function of the ESCRT machinery is to facilitate the sorting and sequestration of ubiquitinated cargo proteins into the internal vesicles of MVBs. This process is crucial for the downregulation of membrane protein signaling and the proper trafficking of membrane proteins to lysosomes for degradation. Beyond its role in MVB biogenesis, the ESCRT machinery is also pivotal in the release of enveloped viruses from infected cells, the repair of damaged plasma membranes, and the separation of daughter cells during cytokinesis.

Components

The ESCRT machinery is composed of several complexes, namely ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III, along with associated proteins such as VPS4, ALIX, and ubiquitin. Each complex plays a distinct role in the ESCRT pathway:

• ESCRT-0 recognizes and sequesters ubiquitinated proteins into clathrin-coated regions of the endosomal membrane.
• ESCRT-I and ESCRT-II work together to deform the membrane inward, forming the initial bud.
• ESCRT-III is responsible for the budding process and the final detachment of the vesicle into the lumen of the MVB.
• VPS4 is an ATPase that disassembles and recycles the ESCRT-III complex.
• ALIX is involved in the abscission stage of cytokinesis and in the budding of certain viruses.

Mechanism

The ESCRT pathway is initiated by the recognition of ubiquitinated cargo by ESCRT-0, which is localized to the endosomal membrane. ESCRT-0 then recruits ESCRT-I, which in turn recruits ESCRT-II to the site. This recruitment leads to the assembly of the ESCRT-III complex, which drives the invagination of the endosomal membrane and the formation of intraluminal vesicles. The ATPase activity of VPS4 is required for the disassembly and recycling of the ESCRT-III complex, allowing for repeated rounds of vesicle formation.

Clinical Significance

Dysfunction in the ESCRT machinery has been linked to various diseases, including neurodegenerative diseases, cancer, and viral infections. The role of ESCRT in viral budding makes it a potential target for antiviral therapies. Additionally, the involvement of ESCRT components in tumor suppression and the regulation of cell death pathways suggests that modulating ESCRT activity could have therapeutic benefits in cancer treatment.

See Also

• Multivesicular body
• Ubiquitin
• Cytokinesis
• Autophagy