Roles of Ubiquitinylation in Proteolysis and Cellular Regulation

Wilkinson, K. D.

doi:10.1146/annurev.nutr.15.1.161

Cited by 45 publications

(63 citation statements)

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“…Ubiquitin is a 76-amino acid, highly conserved protein that is universally present in eukaryotic cells. Its covalent attachment to a variety of cellular proteins is catalyzed by a family of ubiquitin-conjugating (E2) enzymes that mediate the formation of an isopeptide bond between the carboxyl-terminal glycine of ubiquitin and the • amino group of a lysine residue in an acceptor protein (Hershko and Ciechanover, 1992;Wilkinson, 1995). Equally important to their conjugation, ubiquitin subunits are also removed by ubiquitin carboxyl-terminal hydrolases (isopeptidases), making ubiquitination a reversible and regulatable posttranslational modification (Hershko and Ciechanover, 1992;Wilkinson, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Its covalent attachment to a variety of cellular proteins is catalyzed by a family of ubiquitin-conjugating (E2) enzymes that mediate the formation of an isopeptide bond between the carboxyl-terminal glycine of ubiquitin and the • amino group of a lysine residue in an acceptor protein (Hershko and Ciechanover, 1992;Wilkinson, 1995). Equally important to their conjugation, ubiquitin subunits are also removed by ubiquitin carboxyl-terminal hydrolases (isopeptidases), making ubiquitination a reversible and regulatable posttranslational modification (Hershko and Ciechanover, 1992;Wilkinson, 1995). While ubiquitinmediated proteolysis is the best-studied function of ubiquitin conjugation, it has also been implicated in regulating a host of other cellular processes, including endocytosis and vacuolar targeting, protein kinase activation, protein import into mitochondria, and peroxisome biogenesis (Ciechanover, 1994;Wilkinson, 1995;Chen et al, 1996;Egner and Kuchler, 1996;Galan et al, 1996;Hicke and Riezman, 1996;Roth and Davis, 1996;Strous et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…6 B). This double glycine is essential for the proteolytic processing of ubiquitin precursors and for the recycling of posttranslationally synthesized polyubiquitin (Hershko and Ciechanover, 1992;Wilkinson, 1995). Similar to ubiquitin Figure 5.…”

Section: Identification Of a Novel Ubiquitin-like Polypeptide Associamentioning

confidence: 99%

“…Using the permeabilized cell assay in conjunction with biochemical fractionation of cytosolic extracts, four factors required for nuclear import have been purified and characterized Blobel, 1993, 1994;Adam and Adam, 1994;G6rlich et al, 1994, 1995 1. Abbreviations used in this paper: BRL, buffalo rat liver (cells); EST, expressed sequence tagged; NEM, N-ethylmaleimide; NPC, nuclear pore complex; PCLF, pore complex lamina formation.…”

mentioning

confidence: 99%

“…Targeting of a subpopulation of RCC1 and/or RanGAP1 to the NPC could potentially be regulated by modification of these factors. One modification that specifies protein targeting is ubiquitination, which is a posttranslational modification involving the covalent ligation of the carboxyl terminus of ubiquitin to internal lysine residues in a host of intracellular proteins (Hershko and Ciechanover, 1992;Wilkinson, 1995). Whereas the primary fate of ubiquitinated proteins is degradation by the 26S proteosome (Ciechanover, 1994;Jentsch and Schlenker, 1995), it has long been recognized that ubiquitination is likely to have roles beyond proteolysis.…”

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confidence: 99%

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A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex.

Matunis

Coutavas

Blobel

1996

The Journal of Cell Biology

1,082

973

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Abstract. Ran is a nuclear Ras-like GTPase that is required for the bidirectional transport of proteins and ribonucleoproteins across the nuclear pore complex (NPC). A key regulator of the Ran GTP/GDP cycle is the 70:kD Ran-GTPase-activating protein RanGAP1. Here, we report the identification and localization of a novel form of RanGAP1. Using peptide sequence analysis and specific mAbs, RanGAP1 was found to be modified by conjugation to a ubiquitin-like protein.Immunoblot analysis and immunolocalization by light and EM demonstrated that the 70-kD unmodified form of RanGAP1 is exclusively cytoplasmic, whereas the 90-kD modified form of RanGAP1 is associated with the cytoplasmic fibers of the NPC. The modified form of RanGAP1 also appeared to associate with the mitotic spindle apparatus during mitosis. These findings have specific implications for Ran function and broad implications for protein regulation by ubiquitin-like modifications. Moreover, the variety and function of ubiquitin-like protein modifications in the cell may be more diverse than previously realized.T RANSPORT of macromolecules across the nuclear envelope occurs bidirectionally through nuclear pore complexes (NPCs) 1, large supramolecular assemblies that span both membranes of the nuclear envelope (Rout and Wente, 1994). Whereas small ions and metabolites can passively diffuse through the NPC, most proteins and ribonucleoproteins are transported across the NPC by a signal-and energy-dependent mechanism. Dissection of the events culminating in nuclear import has been aided by the development of a permeabilized cell system that has made possible the identification of soluble cytosolic factors required for nuclear import (Adam et al., 1990), and more recently by the development of solution binding assays that use recombinant transport factors and nucleoporins .Using the permeabilized cell assay in conjunction with biochemical fractionation of cytosolic extracts, four factors required for nuclear import have been purified and characterized (Moore and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of a Novel Ubiquitin-like Polypeptide Associamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex.

Matunis

Coutavas

Blobel

1996

The Journal of Cell Biology

1,082

973

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Transgene-coded chimeric proteins as reporters of intracellular proteolysis: Starvation-induced catabolism of alacZ fusion protein in muscle cells ofCaenorhabditis elegans

et al. 1997

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The product of an integrated transgene provides a convenient and cell-specific reporter of intracellular protein catabolism in 103 muscle cells of the nematode Caenorhabditis elegans. The transgene is an in-frame fusion of a 5'-region of the C. elegans unc-54 (muscle myosin heavy-chain) gene to the lacZ gene of Escherichia coli [Fire and Waterston (1989): EMBO J 8:3419-3428], encoding a 146-kDa fusion polypeptide that forms active beta-galactosidase tetramers. The protein is stable in vivo in well-fed animals, but upon removal of the food source it is inactivated exponentially (t1/2 = 17 h) following an initial lag of 8 h. The same rate constant (but no lag) is observed in animals starved in the presence of cycloheximide, implying that inactivation is catalyzed by pre-existing proteases. Both the 146-kDa fusion polypeptide (t1/2 = 13 h) and a major 116-kDa intermediate (t1/2 = 7 h) undergo exponential physical degradation after a lag of 8 h. Degradation is thus paradoxically faster than inactivation, and a number of characteristic immunoreactive degradation intermediates, some less than one-third the size of the parent polypeptide, are found in affinity-purified (active) protein. Some of these intermediates are conjugated to ubiquitin. We infer that the initial proteolytic cleavages occur in the cytosol, possibly by a ubiquitin-mediated proteolytic pathway and do not necessarily inactivate the fusion protein tetramer.

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Transgene‐coded chimeric proteins as reporters of intracellular proteolysis: Starvation‐induced catabolism of a lacZ fusion protein in muscle cells of Caenorhabditis elegans

et al. 1997

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Roles of Ubiquitinylation in Proteolysis and Cellular Regulation

Cited by 45 publications

References 0 publications

A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex.

A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex.

Transgene-coded chimeric proteins as reporters of intracellular proteolysis: Starvation-induced catabolism of alacZ fusion protein in muscle cells ofCaenorhabditis elegans

Transgene‐coded chimeric proteins as reporters of intracellular proteolysis: Starvation‐induced catabolism of a lacZ fusion protein in muscle cells of Caenorhabditis elegans

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