Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome pathway is the principal mechanism for the turnover of short-lived proteins in eukaryotic cells. In this pathway, the covalent ligation of ubiquitin to the substrate is a signal for recognition by the 26S proteasome. Recent studies indicate that targeting of substrates of the ubiquitin pathway to the proteasome is usually accomplished by the ligation of a polyubiquitin chain assembled through K48-G76 isopeptide bonds, rather than by ligation of monoubiquitin. In addition to providing benefits in signal generation, recognition, and persistence, assigning the proteolytic targeting function to a specific specific type of polyubiquitin chain may allow monoubiquitin or polyubiquitin chains of novel structures to serve distinct targeting functions. Besides polyubiquitinated substrates, the proteasome also degrades an unknown number of proteins that are recognized without undergoing ubiquitination. Ornithine decarboxylase is the prototype ubiquitin-independent substrate; it is targeted to the proteasome through noncovalent interaction with a specific protein factor known as antizyme. The existence of ubiquitin-independent substrates of the proteasome raises important questions about the nature of the substrate- and proteasome-based elements that cooperate to bring about the targeting of substrates to this novel proteolytic complex.
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PMID:Targeting of substrates to the 26S proteasome. 936 41

The modification of cytosolic proteins with polyubiquitin chains targets them for recognition and degradation by the multisubunit proteolytic particle, the 26S proteasome. Membrane proteins are also substrates for ubiquitination. Integral membrane proteins of the endoplasmic reticulum are ubiquitinated and destroyed by the proteasome. However, it has been shown recently that the ubiquitination of Saccharomyces cerevisiae plasma membrane proteins signals their degradation by the proteolytic system in the lysosome-like vacuole. Ubiquitination of several different classes of cell surface proteins serves as a signal for their entry into the endocytic pathway; this leads to their transport to the vacuole, where they are permanently inactivated by degradation. In yeast, ubiquitin has been implicated as an internalization signal for most, if not all, endogenous plasma membrane proteins that are known to be endocytosed. Ubiquitin-dependent internalization has been best characterized for two proteins: the mating pheromone alpha-factor receptor and the uracil permease. Some mammalian cell surface receptors are also ubiquitinated at the plasma membrane. Ubiquitination machinery is required for ligand-induced endocytosis of the growth hormone receptor, suggesting that ubiquitin-dependent endocytosis and sorting is also an important regulatory process in mammalian cells. Mammalian receptors may also be down-regulated through the degradation of their cytosolic domains by a proteasome-dependent pathway.
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PMID:Ubiquitin-dependent internalization and down-regulation of plasma membrane proteins. 940 40

The principal targeting signal used in the ubiquitin-proteasome degradation pathway is a homopolymeric, K48-linked polyubiquitin chain: the chain is recognized by a specific factor(s) in the 19S regulatory complex of the 26S proteasome, while the substrate is degraded by the 20S catalytic complex. We have previously presented evidence implicating the side chains of L8, I44, and V70 in the recognition of K48-linked chains. In the crystal structure of tetraubiquitin, these side chains form a repeating, surface-exposed hydrophobic patch. To test the hypothesis that a close-packing interaction involving this patch is important for the chain recognition, residue 8 was mutated to a series of smaller aliphatic amino acids (G, A, V). The effects of these mutations were first investigated in rabbit reticulocyte fraction II; even the severest truncating mutation (L8G) had only a modest inhibitory effect on the degradation of a model substrate (125I-lactalbumin). We show that these steady-state degradation data substantially underestimate the deleterious effects of these mutations on chain recognition by the proteasome, because the recognition step does not contribute to rate limitation in the fraction II system. Much stronger inhibition was observed when chain binding was measured in a competition assay using purified 26S proteasomes, and the change in binding free energy depended linearly on the surface area of the side chain. This behavior is consistent with a mode of binding in which the hydrophobic effect makes a favorable contribution; i.e., one or more L8 side chains is shielded from solvent when the chain binds to the 19S complex. A similar linear dependence of binding energy on side chain area was observed for chain binding to the 19S subunit known as S5a (as assayed using recombinant S5a bound to nickel beads). Octa-ubiquitin (K0.5 = 1.6 microM) bound to S5a 4.2-fold more tightly than tetra-ubiquitin; this is similar to the factor of 5. 8-fold relating the affinities of the same two chains for the 26S proteasome. Altogether, these findings indicate that the interaction of K48-linked chains with the 19S complex is substantially similar to the interaction of chains with isolated S5a. The results further suggest that the hydrophobic patch is part of a minimum element which allows for specific recognition of the polyubiquitin degradation signal by the 26S proteasome.
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PMID:The hydrophobic effect contributes to polyubiquitin chain recognition. 948 44

The human immunodeficiency virus type 1 (HIV-1) vpu gene encodes a type I anchored integral membrane phosphoprotein with two independent functions. First, it regulates virus release from a post-endoplasmic reticulum (ER) compartment by an ion channel activity mediated by its transmembrane anchor. Second, it induces the selective down regulation of host cell receptor proteins (CD4 and major histocompatibility complex class I molecules) in a process involving its phosphorylated cytoplasmic tail. In the present work, we show that the Vpu-induced proteolysis of nascent CD4 can be completely blocked by peptide aldehydes that act as competitive inhibitors of proteasome function and also by lactacystin, which blocks proteasome activity by covalently binding to the catalytic beta subunits of proteasomes. The sensitivity of Vpu-induced CD4 degradation to proteasome inhibitors paralleled the inhibition of proteasome degradation of a model ubiquitinated substrate. Characterization of CD4-associated oligosaccharides indicated that CD4 rescued from Vpu-induced degradation by proteasome inhibitors is exported from the ER to the Golgi complex. This finding suggests that retranslocation of CD4 from the ER to the cytosol may be coupled to its proteasomal degradation. CD4 degradation mediated by Vpu does not require the ER chaperone calnexin and is dependent on an intact ubiquitin-conjugating system. This was demonstrated by inhibition of CD4 degradation (i) in cells expressing a thermally inactivated form of the ubiquitin-activating enzyme E1 or (ii) following expression of a mutant form of ubiquitin (Lys48 mutated to Arg48) known to compromise ubiquitin targeting by interfering with the formation of polyubiquitin complexes. CD4 degradation was also prevented by altering the four Lys residues in its cytosolic domain to Arg, suggesting a role for ubiquitination of one or more of these residues in the process of degradation. The results clearly demonstrate a role for the cytosolic ubiquitin-proteasome pathway in the process of Vpu-induced CD4 degradation. In contrast to other viral proteins (human cytomegalovirus US2 and US11), however, whose translocation of host ER molecules into the cytosol occurs in the presence of proteasome inhibitors, Vpu-targeted CD4 remains in the ER in a transport-competent form when proteasome activity is blocked.
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PMID:CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. 949 87

Ubiquitin conjugation is known to target protein substrates primarily to degradation by the proteasome or via the endocytic route. Here we describe a novel protein modification pathway in yeast which mediates the conjugation of RUB1, a ubiquitin-like protein displaying 53% amino acid identity to ubiquitin. We show that RUB1 conjugation requires at least three proteins in vivo. ULA1 and UBA3 are related to the N- and C-terminal domains of the E1 ubiquitin-activating enzyme, respectively, and together fulfil E1-like functions for RUB1 activation. RUB1 conjugation also requires UBC12, a protein related to E2 ubiquitin-conjugating enzymes, which functions analogously to E2 enzymes in RUB1-protein conjugate formation. Conjugation of RUB1 is not essential for normal cell growth and appears to be selective for a small set of substrates. Remarkably, CDC53/cullin, a common subunit of the multifunctional SCF ubiquitin ligase, was found to be a major substrate for RUB1 conjugation. This suggests that the RUB1 conjugation pathway is functionally affiliated to the ubiquitin-proteasome system and may play a regulatory role.
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PMID:A novel protein modification pathway related to the ubiquitin system. 954 34

Proteolytic digestion of ryanodine receptor (RyR) purified from skeletal muscle generated 25 short peptides. The amino acid sequences of two, 'KC5' and 'KC7', were absent from the RyR primary structure deduced by cDNA cloning. The sequence of KC7 corresponded to the N-terminus of the 12 kDa FK506-binding protein, which associates with the RyR and modulates its Ca2+ release channel (CRC) function. The sequence of KC5 was not similar to any proteins in the databases searched at that time. In the present study, the sequence of KC5 was compared to proteins in the current Swissprot database release and corresponds most closely to S5a, a proteasome subunit. Since S5a targets the 26S proteasome to polyubiquitinated proteins, and inositol 1,4,5-trisphosphate receptors, a related class of CRC, are down-regulated by a polyubiquitin-dependent mechanism in hormone stimulated cells, the abundance of RyRs may be controlled by association with this regulatory subunit.
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PMID:Possible regulation of the skeletal muscle ryanodine receptor by a polyubiquitin binding subunit of the 26S proteasome. 957 Nov 68

The ubiquitin-proteasome pathway (UPP) regulates critical cell processes, including the cell cycle, cytokine-induced gene expression, differentiation, and cell death. Recently we demonstrated that this pathway responds to oxidative stress in mammalian cells and proposed that activities of ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzymes (E2s) are regulated by cellular redox status (i.e., GSSG:GSH ratio). To test this hypothesis, we altered the GSSG:GSH ratio in retinal pigment epithelial cells with the thiol-specific oxidant, diamide, and assessed activities of the UPP. Treatment of cells with diamide resulted in a dose-dependent increase in the GSSG:GSH ratio resulting from loss of GSH and a coincident increase in GSSG. Increases in the GSSG:GSH ratio from 0.02 in untreated cells to > or = 0.5 in diamide-treated cells were accompanied by dose-dependent reductions in the levels of endogenous Ub-protein conjugates, endogenous E1-ubiquitin thiol esters, and de novo ubiquitin-conjugating activity. As determined by the ability to form E1-ubiquitin and E2s-ubiquitin thiol esters, E1 and E2s were both inhibited by elevated GSSG:GSH ratios. Inhibition of E1 was associated with the formation of E1-protein mixed disulfides. Activities of E1 and E2s gradually recovered to preoxidation levels, coincident with gradual recovery of the GSSG:GSH ratio. These data support S-thiolation/dethiolation as a mechanism regulating E1 and E2 activities in response to oxidant insult. Ubiquitin-dependent proteolytic capacity was regulated by the GSSG:GSH ratio in a manner consistent with altered ubiquitin-conjugating activity. However, ubiquitin-independent proteolysis was unaffected by changes in the GSSG:GSH ratio. Potential adaptive and pathological consequences of redox regulation of UPP activities are discussed.
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PMID:Redox regulation of ubiquitin-conjugating enzymes: mechanistic insights using the thiol-specific oxidant diamide. 957 83

The ubiquitin-proteasome proteolytic pathway has recently been reported to be of major importance in the breakdown of skeletal muscle proteins. The first step in this pathway is the covalent attachment of polyubiquitin chains to the targeted protein. Polyubiquitylated proteins are then recognized and degraded by the 26S proteasome complex. In this review, we critically analyse recent findings in the regulation of this pathway, both in animal models of muscle wasting and in some human diseases. The identification of regulatory steps of ubiquitin conjugation to protein substrates and/or of the proteolytic activities of the proteasome should lead to new concepts that can be used to manipulate muscle protein mass. Such concepts are essential for the development of anti-cachectic therapies for many clinical situations.
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PMID:Ubiquitin-proteasome-dependent proteolysis in skeletal muscle. 963 89

To identify factors involved in the expression of ligand-gated ion channels, we expressed nicotinic acetylcholine receptors in HEK cells to characterize roles for oligosaccharide trimming, calnexin association, and targeting to the proteasome. The homologous subunits of the acetylcholine receptor traverse the membrane four times, contain at least one oligosaccharide, and are retained in the endoplasmic reticulum until completely assembled into the circular arrangement of subunits of delta-alpha-gamma-alpha-beta to enclose the ion channel. We previously demonstrated that calnexin is associated with unassembled subunits of the receptor, but appears to dissociate when subunits are assembled in various combinations. We used the glucosidase inhibitor castanospermine to block oligosaccharide processing, and thereby inhibit calnexin's interaction with the oligosaccharides in the receptor subunits. Castanospermine treatment reduces the association of calnexin with the alpha-subunit of the receptor, and diminishes the intracellular accumulation of unassembled receptor subunit protein. However, treatment with castanospermine does not appear to alter subunit folding or assembly. In contrast, co-treatment with proteasome inhibitors and castanospermine enhances the accumulation of polyubiquitin-conjugated alpha-subunits, and generally reverses the castanospermine induced loss of alpha-subunit protein. Co-transfection of cDNAs encoding the alpha- and delta-subunits, which leads to the expression of assembled alpha- and delta- subunits, also inhibits the loss of alpha-subunits expressed in the presence of castanospermine. Taken together, these observations indicate that calnexin association reduces the degradation of unassembled receptor subunits in the ubiquitin-proteasome pathway.
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PMID:Inhibition of glucose trimming with castanospermine reduces calnexin association and promotes proteasome degradation of the alpha-subunit of the nicotinic acetylcholine receptor. 964 71

Modification of an S. cerevisiae G protein-coupled receptor with ubiquitin is required for its ligand-stimulated internalization. We now demonstrate that monoubiquitination on a single lysine residue is sufficient to signal receptor internalization, a modification distinct from that required for proteasome recognition. Formation of a polyubiquitin chain is not necessary, as demonstrated by the ability of mutant ubiquitins that lack lysine residues to serve as efficient internalization signals. Fusion of ubiquitin in-frame to a receptor that lacks cytoplasmic tail lysines also promotes rapid receptor internalization, indicating that ubiquitin itself and not a specific type of linkage to the receptor acts as an internalization signal. Thus, we have defined a cellular function for monoubiquitination in alpha-factor receptor endocytosis.
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PMID:A function for monoubiquitination in the internalization of a G protein-coupled receptor. 965 16


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