Ubiquitin endocytosis

Horak J, Wolf DH (1997) Catabolite inactivation of the galactose transporter in the yeast Saccharomyces cerevisiae Ubiquitination, endocytosis and degradation in the vaccuole. J Bacteriol 179 1541-1549... 

Roth AF, Sullivan DM, Davis NG (1998) A large PEST-like sequence directs the ubiquitination, endocytosis and vacuolar degradation of the yeast a-factor receptor.) Cell Biol 142 946-961... 

Ubiquitin/Proteasome. Figure 2 Functional consequences of ubiquitin linkage. Substrates (blue bars) are linked via lysine residues (K) to ubiquitin or ubiquitin chains, (a) Attachment of chains connected via Lysines in position 48 of ubiquitin (K48) targets substrates for proteasomal degradation. In contrast modification of one (b) or multiple (c) lysines by a single ubiquitin molecule mediates novel protein interactions or initiates endocytosis. Conjugation of K63-linked polyubiquitin (d) alters protein function and can also serve as a signal for endocytosis. 

Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315 201-205... 

CoscoY, L., D. J. Sanchez, and D. Ganem, a novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. / Cell Biol, 2001, 155(7), 1265-73. 

Hicke, L. and Riezman, H. Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cdl 1996, 84, 277-87. 

Haglund, K. et al. Multiple mono-ubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 2003, 5, 461-6. 

KoUing, R. and Hohenberg, C.P., 1994, The ABC-Transporter Ste6 accumulates in the plasma membrane in a ubiquitinated form in endocytosis mutants. EMBOJ., 13 3261-3271. 

Ubiquitination reaction is reversible like phosphorylation until the ubiquitinated protein is committed to degradation by the proteasome. The reversibility is less clear with respect to endocytotic degradation, that is, internalization of plasma membrane proteins through endocytosis and their degradation through the lysosome. 

Figure 8 Ubiquitin and endocytosis. Receptors on the plasma membrane undergo monoubiquitination as a result of ligand (e.g., neurotransmitter). Ubiquitinated receptors bind to proteins called epsins, which in turn interact with adaptor proteins (adaptin) bound to clathrin-coated pits. Ubiquitination also functions to sort the internalized membrane protein into early endosomes, which directs them to degradation by lysosome through the multivesicular body. If ubiquitin from the endocytosed receptors is removed by an UBP, the receptor recycles back to the membrane. Proteasome inhibitors block endocytotic degradation of some proteins such as glutamate receptor subunits indicating a possible role for the proteasome.

Due to the close structural and functional relationships between yeast and mammalian endocytic processes, it is worthwhile to review the action of some of the major molecular players in endocytosis of yeast membrane proteins. These are the ubiquitin ligase Rsp5p (Nedd4 in mammals), Panlp, the putative ortholog of Eps-15 of mammals, and Vps23p, whose ortholog is Tsg-101. 

Panlp- Panlp in yeast, and its mammalian homologue, EGFR protein substrate 15 (EpslS), are essential for normal endocytosis (Carbone et al. 1997 Benmerah et al. 1998 Wendland and Emr 1998). Although these proteins are associated with clathrin complexes and genetic evidence raised the possibility that Panlp may act as an adaptor connecting RspSp to potential ubiquitination substrates, physical associations between RspSp and Panlp have not been detected. In mammalian cells, EpslS is tyrosine-phosphorylated and mono-ubiquitinated upon EGF stimulation (van Delft et al. 1997). The tyrosine-phosphorylation of the protein may play a role in... 

Ligand-Induced Ubiquitination and Endocytosis of Receptor Proteins... 

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