Abstract
Lysosomal degradation of ubiquitinated transmembrane protein receptors (cargo) relies on the function of Endosomal Sorting Complex Required for Transport (ESCRT) protein complexes. The ESCRT machinery is comprised of five unique oligomeric complexes with distinct functions. Target of Myb1 (TOM1) is an ESCRT protein involved in the initial steps of endosomal cargo sorting. To exert its function, TOM1 associates with ubiquitin moieties on the cargo via its VHS and GAT domains. Several ESCRT proteins, including TOLLIP, Endofin, and Hrs, have been reported to form a complex with TOM1 at early endosomal membrane surfaces, which may potentiate the role of TOM1 in cargo sorting. More recently, it was found that TOM1 is involved in other physiological processes, including autophagy, immune responses, and neuroinflammation, which crosstalk with its endosomal cargo sorting function. Alteration of TOM1 function has emerged as a phosphoinositide-dependent survival mechanism for bacterial infections and cancer progression. Based on current knowledge of TOM1-dependent cellular processes, this review illustrates how TOM1 functions in coordination with an array of protein partners under physiological and pathological scenarios.
Highlights
To attenuate signaling, cells are able to ubiquitinate and remove cell-surface membrane proteins by a concerted process involving internalization of the proteins by endocytosis, followed by delivery to the endolysosomal membrane system for proteolysis
Together with Target of Myb1 (TOM1), many other ubiquitin-binding modular proteins have been grouped within the Endosomal Sorting Complex Required for Transport (ESCRT)-0 family in mammals
Some recognize Lys48-linked ubiquitin moieties, whereas others like TOM1 and Toll-interacting protein (TOLLIP) prefer Lys63-linked over Lys-48-linked polyubiquitin chains covalently attached to protein receptors (Nathan et al, 2013)
Summary
Cells are able to ubiquitinate and remove cell-surface membrane proteins by a concerted process involving internalization of the proteins by endocytosis, followed by delivery to the endolysosomal membrane system for proteolysis. In both animals and plants, degradation of cargo relies on the assembly of the ESCRT proteins at the surface of early endosomes, but complex initiation might occur at the plasma membrane (Mayers et al, 2013). Each of the ESCRT0, ESCRT-I, and ESCRT-II complexes is composed of proteins with ubiquitin-binding domains for cargo recognition and phosphatidylinositol 3-phosphate (PtdIns3P)-binding domains for endosomal membrane anchoring.
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