As a mechanism of signal attenuation, receptors for
growth factors,
peptide hormones and
cytokines are internalized in response to
ligand binding, followed by degradation in lysosomes. Receptor ubiquitination is a key signal for such downregulation, and four
protein complexes known as
endosomal sorting complex required for transport (ESCRT)-0, -I, -II and -III have been identified as the machinery required for degradative endosomal sorting of ubiquitinated
membrane proteins in yeast and metazoans. Three of these complexes contain
ubiquitin-binding domains whereas
ESCRT-III instead recruits
deubiquitinating enzymes. The concerted action of the ESCRTs not only serves to sort ubiquitinated cargo but is also thought to cause inward vesiculation of endosomal membranes, thereby mediating biogenesis of multivesicular endosomes (MVEs). Because
ligand-mediated receptor downregulation plays an important role in signal attenuation, it is not surprising that dysfunction of ESCRT components is associated with disease. In this review we discuss the possible roles of ESCRTs in protection against
cancer,
neurodegenerative diseases and
bacterial infections, and we highlight the fact that many RNA viruses exploit the
ESCRT machinery for the final abscission step of their budding from cells. We also review the additional functions of ESCRT
proteins in cytokinesis and discuss how these may be related to ESCRT-associated pathologies.