Ubiquitin and endocytic protein sorting.
Ubiquitin plays a fundamental role not only in proteasome-mediated protein degradation but also in the targeting of membrane proteins for degradation inside the lysosome. Ubiquitination provides a key signal for endosomal sorting of membrane proteins into the MVB (multi-vesicular body), which delivers its cargo to the proteolytic interior of the lysosome. Attachment of single ubiquitin molecules, rather than ubiquitin chains, to one or multiple lysines of the cytoplasmic domains of many growth factor receptors, ion channels and other membrane transporters is sufficient to target these proteins to a complex sorting apparatus on the endosome. This machinery selects ubiquitinated proteins for lysosomal sorting through consecutive interactions with a variety of ubiquitin-binding domains. The major ubiquitin ligase (E3) responsible for ubiquitination in this pathway in yeast is the HECT [homologous to E6-AP (E6-associated protein) C-terminus]-ligase, Rsp5, whereas in mammalian cells the RING (really interesting new gene)-ligase Cbl has been implicated in the down-regulation of several RTKs (receptor tyrosine kinases). Ubiquitinated receptors can be rescued from degradation by the activity of DUBs (deubiquitinating enzymes), which may provide a proofreading mechanism that enhances the fidelity of this sorting and degradation process. DUBs also allow for recycling of the ubiquitin moieties from proteins prior to their final commitment to the MVB and lysosome interior.
Urbé
Sylvie
S
Physiological Laboratory, University of Liverpool, Crown St., Liverpool L69 3BX, UK. urbe@liv.ac.uk
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; C464563:Hse1 protein, S cerevisiae; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C109775:STAM protein, human; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C119627:VPS27 protein, S cerevisiae; D033921:Vesicular Transport Proteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D044767:Ubiquitin-Protein Ligases