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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inclusions isolated from several neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by ubiquitin-positive proteinaceous aggregates. Employing confocal and immunoelectron microscopy, we find that the ubiquitin-associating protein sequestosome1/p62, co-localizes to aggregates isolated from AD but not control brain, along with the E3 ubiquitin ligase, TRAF6. This interaction could be recapitulated by co-transfection in HEK293 cells. Employing both in vitro and in vivo approaches, tau was found to be a substrate of the TRAF6, possessing lysine 63 polyubiquitin chains. Moreover, tau recovered from brain of TRAF6 knockout mice, compared with wild type, was not ubiquitinated. Tau degradation took place through the ubiquitin-proteasome pathway and was dependent upon either the K63-polyubiquitin chains or upon p62. In brain lysates of p62 knockout mice, tau fails to co-interact with Rpt1, a proteasomal subunit, thereby indicating a requirement for p62 shuttling of tau to the proteasome. Our results demonstrate that p62 interacts with K63-polyubiquitinated tau through its UBA domain and serves a novel role in regulating tau proteasomal degradation. We propose a model whereby either a decline in p62 expression or a decrease in proteasome activity may contribute to accumulation of insoluble/aggregated K63-polyubiquitinated tau.
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PMID:Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. 1595 62

Modification of cellular proteins with a small protein called ubiquitin has profound effects on their activities. Ubiquitin is covalently attached to lysine residues of acceptor proteins through the concerted action of E1 ubiquitin-activating enzyme, E2 ubiquitin-carrier proteins and E3 ligases. Mammalian cells contain a large number of E3 ligases, which determine the specificity of ubiquitination reactions. Recent studies have revealed that ubiquitination can be reversed by deubiquitinating enzymes that release ubiquitin monomers from modified proteins. Signalling networks that control inflammation are tightly regulated by a multitude of ubiquitination and deubiquitination reactions. This article begins by summarising current understanding of these pathways at a molecular level, and then focuses on the importance of ubiquitination and deubiquitination during the regulation of the pro-inflammatory transcription factor NF-kappaB. Finally, the potential for ubiquitin modifications to be targeted by novel classes of anti-inflammatory drugs is discussed.
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PMID:Regulation of pro-inflammatory signalling networks by ubiquitin: identification of novel targets for anti-inflammatory drugs. 1596 57

Ubiquitin is important for the release of human immunodeficiency virus type 1 (HIV-1) and several other retroviruses, but the functional significance of Gag ubiquitination is unknown. To address this problem, we decided to analyze Gag ubiquitination in detail. A low percentage of the HIV-1 p6 protein has previously been shown to be ubiquitinated, and published mutagenesis data suggested that Gag ubiquitination is largely lost upon mutation of the two lysine residues in p6. In this study, we show that Gag proteins lacking the p6 domain or the two lysine residues within p6 are ubiquitinated at levels comparable to those of the wild-type Gag protein. We detected monoubiquitinated forms of the matrix (MA), capsid (CA), and nucleocapsid (NC) proteins in mature virus preparations. Protease digestion of Gag polyproteins extracted from immature virions indicated that ubiquitinated MA, CA, and possibly NC are as abundant as ubiquitinated p6. The HIV-1 late-domain motifs PTAP and LRSLF were not required for Gag ubiquitination, and mutation of the PTAP motif even resulted in an increase in the amount of Gag-Ub conjugates detected. Finally, at steady state, ubiquitinated Gag proteins were not enriched in either membrane-associated or virus-derived Gag fractions. In summary, these results indicate that HIV-1 Gag can be monoubiquitinated in all domains and that ubiquitination of lysine residues outside p6 may thus contribute to viral release and/or infectivity.
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PMID:Analysis of human immunodeficiency virus type 1 Gag ubiquitination. 1599 8

The cytoplasm to vacuole (Cvt) trafficking pathway in S. cerevisiae is a constitutive biosynthetic pathway required for the transport of two vacuolar enzymes, aminopeptidase I (Ape1p) and alpha-mannosidase (Ams1p), to the vacuole. Ape1p and Ams1p bind to their receptor, Atg19p, in the cytosol to form a Cvt complex, which then associates with a membrane structure that envelops the complex before fusing with the vacuolar membrane. Ubiquitin-like modifications are required for both Cvt and macroautophagy, but no role for ubiquitin itself has been described. Here, we show that the deubiquitinating enzyme Ubp3p interacts with Atg19p. Moreover, Atg19p is ubiquitinated in vivo, and Atg19p-ubiquitin conjugates accumulate in cells lacking either Ubp3p or its cofactor, Bre5p. Deletion of UBP3 also leads to decreased targeting of Ape1p to the vacuole. Atg19p is ubiquitinated on two lysine residues, Lys(213) and Lys(216), which, when mutated, reduce the interaction of Atg19p with Ape1p. These results suggest that both ubiquitination and deubiquitination of Atg19p are required for its full function.
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PMID:Atg19p ubiquitination and the cytoplasm to vacuole trafficking pathway in yeast. 1618 26

TRAF2 mediates activation of the transcription factors NF-kappaB and AP1 by TNF. A yeast two-hybrid screen of a human cDNA library identified a ubiquitin specific protease homologue (USP31) as a TRAF2-interacting protein. Two cDNAs encoding for USP31 were identified. One cDNA encodes a 1035-amino acid long isoform of USP31 (USP31, long isoform) and the other a 485-amino acid long isoform of USP31 (USP31S1, short isoform). USP31 and USP31S1 share a common amino terminal region with homology to the catalytic region of known deubiquitinating enzymes. Enzymatic assays demonstrated that USP31 but not USP31S1 possess deubiquitinating activity. Furthermore, it was shown that USP31 has a higher activity towards lysine-63-linked as compared to lysine-48-linked polyubiquitin chains. Overexpression of USP31 in HEK 293T cells inhibited TNFalpha, CD40, LMP1, TRAF2, TRAF6 and IKKbeta-mediated NF-kappaB activation, but did not inhibit Smad-mediated transcription activation. In addition, both USP31 isoforms interact with p65/RelA. Our data support a role for USP31 in the regulation of NF-kappaB activation by members of the TNF receptor superfamily.
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PMID:Human ubiquitin specific protease 31 is a deubiquitinating enzyme implicated in activation of nuclear factor-kappaB. 1621 42

The Myc oncoprotein forms a binary activating complex with its partner protein, Max, and a ternary repressive complex that, in addition to Max, contains the zinc finger protein Miz1. Here we show that the E3 ubiquitin ligase HectH9 ubiquitinates Myc in vivo and in vitro, forming a lysine 63-linked polyubiquitin chain. Miz1 inhibits this ubiquitination. HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes, recruitment of the coactivator p300, and induction of cell proliferation by Myc. HectH9 is overexpressed in multiple human tumors and is essential for proliferation of a subset of tumor cells. Our results suggest that site-specific ubiquitination regulates the switch between an activating and a repressive state of the Myc protein, and they suggest a strategy to interfere with Myc function in vivo.
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PMID:The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. 1626 33

Ubiquitin is synthesized in eukaryotes as a linear fusion with a normal peptide bond either to itself or to one of two ribosomal proteins and, in the latter case, enhances the yield of these ribosomal proteins and/or their incorporation into the ribosome. Such fusions are cleaved rapidly by a variety of deubiquitylating enzymes. Expression of heterologous proteins as linear ubiquitin fusions has been found to significantly increase the yield of unstable or poorly expressed proteins in either bacterial or eukaryotic hosts. If expressed in bacterial cells, the fusion is not cleaved due to the absence of deubiquitylating activity and can be purified intact. We have developed an efficient expression system, utilizing the ubiquitin fusion technique and a robust deubiquitylating enzyme, which allows convenient high yield and easy purification of authentic proteins. An affinity purification tag on both the ubiquitin fusion and the deubiquitylating enzyme allows their easy purification and the easy removal of unwanted components after cleavage, leaving the desired protein as the only soluble product. Ubiquitin is also conjugated to epsilon amino groups in lysine side chains of target proteins to form a so-called isopeptide linkage. Either a single ubiquitin can be conjugated or other lysines within ubiquitin can be acceptors for further conjugation, leading to formation of a branched, isopeptide-linked ubiquitin chain. Removal of these ubiquitin moieties or chains in vitro would be a valuable tool in the ubiquitinologists tool kit to simplify downstream studies on ubiquitylated targets. The robust deubiquitylating enzyme described earlier is also very useful for this task.
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PMID:Using deubiquitylating enzymes as research tools. 1627 57

Ubiquitin can be conjugated to lysine residues of other ubiquitin molecules to form polymers called polyubiquitin chains. Ubiquitin has seven lysine residues, creating the potential for seven distinct types of chains, at least five of which have been observed in vitro or in vivo. A subset of these chains mediates substrate targeting to proteasomes, whereas other types of chains have been implicated in nonproteolytic signaling pathways. In this chapter, we outline chemical and genetic strategies that can be used to deduce (or control) the structures of polyubiquitin chains in vitro and in living cells.
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PMID:Chemical and genetic strategies for manipulating polyubiquitin chain structure. 1633 45

Many intracellular signaling processes depend on the modification of proteins with polymers of the conserved 76-residue protein ubiquitin. The ubiquitin units in such polyubiquitin chains are connected by isopeptide bonds between a specific lysine residue of one ubiquitin and the carboxyl group of G76 of the next ubiquitin. Chains linked through K48-G76 and K63-G76 bonds are the best characterized, signaling proteasome degradation and nonproteolytic outcomes, respectively. The molecular determinants of polyubiquitin chain recognition are under active investigation; both the chemical structure and the length of the chain can influence signaling outcomes. In this article, we describe the protein reagents necessary to produce K48- and K63-linked polyubiquitin chains and the use of these materials to produce milligram quantities of specific-length chains for biochemical and biophysical studies. The method involves reactions catalyzed by linkage-specific conjugating factors, in which proximally and distally blocked monoubiquitins (or chains) are joined to produce a particular chain product in high yield. Individual chains are then deblocked and joined in another round of reaction. Successive rounds of deblocking and synthesis give rise to a chain of the desired length.
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PMID:Controlled synthesis of polyubiquitin chains. 1633 46

Ubiquitin (Ub) regulates important cellular processes through covalent attachment to its substrates. Distinct fates are bestowed on multi-Ub chains linked through different lysine residues. Ub contains seven conserved lysines, all of which could be used for multi-Ub chain formation. K29 and K48 are the signals for proteasome-mediated proteolysis. Multi-Ub chains linked through K63 have nonproteolytic functions. Studies of Ub-binding factors are likely the key to understanding diverse functions of the Ub molecule. Yeast two-hybrid assay can be a powerful approach to dissect the interaction between Ub and its binding proteins and also the function of these Ub-chain binding proteins in vivo.
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PMID:Analysis of ubiquitin chain-binding proteins by two-hybrid methods. 1633 54


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