Regulation of Endocytic Trafficking and Signalling by Deubiquitylating Enzymes

As the major route by which activated Receptor Tyrosine Kinases are degraded, the endolysosomal pathway may be seen as a tumour suppressor pathway. The appendage of ubiquitin chains to activated receptors provides a sorting signal for sorting into multivesicular bodies which go on to fuse directly with lysosomes. Deubiquitylating (DUB) activities, such as the endosome-localised AMSH and USP8, can favour recycling of receptors by reducing this active sorting into MVBs. These enzymes have an overlapping set of binding partners at the endosome, which include both early- and late-acting components of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. The exact interplay between these enzymes is still under debate. The consequences of depletion can be complex and need to be interpreted with care. Generically endosomal DUBs can influence receptor trafficking by direct deubiquitylation of receptors or associated proteins, by stabilisation of sorting factors or by contributing to free ubiquitin homeostasis by recycling ubiquitin once a MVB cargo molecule has been committed to degradation. We propose that a single endosomal DUB may carry out multiple functions depending on the suite of interactions being employed. Recent studies have provided further examples of DUBs which may associate with endosomes in a transient manner to influence the sorting of RTKs but also other types of receptors, such as GPCRs and various channels.