Physical and Functional Interactions of Monoubiquitylated Transactivators with the Proteasome

Archer, Chase T.; Burdine, Lyle; Liu, Bo; Ferdous, Anwarul; Johnston, Stephen Albert; Kodadek, Thomas

doi:10.1074/jbc.m803075200

Cited by 34 publications

(52 citation statements)

References 38 publications

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“…Although the exact mechanisms by which the 19 S RP participates in substrate degradation remain to be completely elucidated (64), Rpn1 and Rpn2 are known to play a major role in processing and unfolding polyubiquitin chains and in transferring ubiquitinated proteins to the 20 S core where they are degraded (7,(11)(12)(13)(14)(15). Recent studies, as well as the present experiments, demonstrated that association of the 20 S CP with Rpn2 results in enhanced 20 S activity (7).…”

Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

“…The 19 S RP consists of a lid and base subcomplex, with the base subcomplex, including the nonenzymatic Rpn1 and Rpn2 toroids, surrounded by six AAA-type ATPases. Rpn1 and Rpn2 appear to play a major regulatory role by modulating the translocation and subsequent degradation of ubiquitinated substrates in the proteolytic core of the 20 S CP (7,(11)(12)(13)(14)(15).Decreased 26 S proteasomal activity, resulting in the accumulation of intracellular proteins, has been associated with aging (16, 17) and with pathophysiologic processes, including heart failure, neurodegenerative diseases, and alcohol induced liver injury (18 -20). A number of recent studies have shown that time-limited inhibition of the 26 S proteasome is beneficial as a therapeutic intervention for malignancies, such as multiple myeloma, and in reducing inflammation and cell injury associated with ischemia-reperfusion injury and transplantation rejection (21-24).…”

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confidence: 99%

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S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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Although increased intracellular concentrations of hydrogen peroxide (H 2 O 2 ) are associated with inhibition of 26 S proteasomal activity, the mechanisms responsible for such effects have not been well delineated. In the present studies, we found that direct exposure of purified 26 S proteasomes to H 2 O 2 had negligible effects on their activity, whereas incubation with glutathione and H 2 O 2 produced >80% decrease in chymotrypsin-like and trypsin-like activities. Rpn1 and Rpn2, which are subunits of the 19 S regulatory particle, undergo S-glutathionylation after exposure of purified 26 S proteasomes to glutathione and H 2 O 2 , as well as in HEK 293 cells and neutrophils incubated with H 2 O 2 . Increased oxidation of Rpn1 and Rpn2 cysteine thiols was also found in lung extracts from mice in which catalase was inactivated, a condition associated with augmented intracellular concentrations of H 2 O 2 and diminished 26 S proteasomal activity. Although unoxidized Rpn2 enhanced 20 S proteolytic function in vitro, such potentiation was not found when the 20 S core particle was incubated with oxidized Rpn2. The composition of 26 S proteasomes was not altered after exposure to glutathione and H 2 O 2 , with similar amounts of Rpn1 and Rpn2 in control or oxidized 26 S proteasomal complexes. These findings identify S-glutathionylation of Rpn2 as a contributory mechanism for H 2 O 2 -induced inhibition of 26 S proteasomal function.The ubiquitin-proteasomal system is a major pathway for protein degradation and is involved in multiple cellular processes, including cell cycle control, expression of cell surface receptors, and regulation of intracellular levels of structural and regulatory proteins and transcription factors (1-6). The 26 S proteasome is composed of two main components, a proteolytic 20 S core particle (CP) 2 and an ATPase containing 19 S regulatory particle (RP) (7-10). Ubiquitinated proteins are unfolded in the 19 S RP and then translocated into the 20 S CP where they are degraded. The 20 S CP is composed of four heptameric rings of ␣ and ␤ subunits, with the two inner ␤ rings having proteolytic activity. The 19 S RP consists of a lid and base subcomplex, with the base subcomplex, including the nonenzymatic Rpn1 and Rpn2 toroids, surrounded by six AAA-type ATPases. Rpn1 and Rpn2 appear to play a major regulatory role by modulating the translocation and subsequent degradation of ubiquitinated substrates in the proteolytic core of the 20 S CP (7,(11)(12)(13)(14)(15).Decreased 26 S proteasomal activity, resulting in the accumulation of intracellular proteins, has been associated with aging (16, 17) and with pathophysiologic processes, including heart failure, neurodegenerative diseases, and alcohol induced liver injury (18 -20). A number of recent studies have shown that time-limited inhibition of the 26 S proteasome is beneficial as a therapeutic intervention for malignancies, such as multiple myeloma, and in reducing inflammation and cell injury associated with ischemia-reperfusion injury and transplanta...

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

mentioning

confidence: 99%

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S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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“…The detailed mechanism by which ubiquitylation protects Gal4 from the APIS complex has been worked out recently (17).…”

Section: Discussionmentioning

confidence: 99%

“…This activity requires direct interactions between the APIS complex and the activation domain of the Gal4 protein (15). APIS-mediated disruption of Gal4⅐DNA complexes occurs only when Gal4 is not mono-ubiquitylated within the DNA-binding domain (15,17) revealing at least one function of this posttranslational modification (18) to be protection against the destabilizing activity of the proteasomal ATPases. This protective effect involves direct interaction of the mono-ubiquitin moieties with Rpn1 and Rpt1 in the APIS complex, an interaction that disrupts the binding of Rpt4 and Rpt6 to the activation domains of the Gal4 dimer, thus preventing the APIS complex from using the activator as a substrate for its unwinding activity (17).…”

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confidence: 99%

Non-proteolytic Regulation of p53-mediated Transcription through Destabilization of the Activator·Promoter Complex by the Proteasomal ATPases

Kim

Lim

et al. 2009

Journal of Biological Chemistry

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It has been shown previously that sub-complexes of the 26 S proteasome can regulate gene expression via non-proteolytic mechanisms. One such mechanism is the disruption of activator⅐promoter complexes in an ATP-dependent fashion, which was discovered in the context of the yeast Gal4 system. This activity strongly inhibits Gal4-driven gene expression unless the activator is mono-ubiquitylated, which protects it from the ATPases. To address whether this paradigm is also applicable to medically important mammalian transcriptional activators we report here a study of the interaction of the proteasomal ATPases with p53. It is shown that p53 binds directly to the ATPases via its C-terminal tetramerization and regulatory domain and that p53⅐promoter complexes are indeed vulnerable to ATPase-dependent disruption by the ATPase complex in vitro. Knockdown of one of the ATPases, Rpt6, in living cells results in increased occupancy of the p21 waf1 promoter by p53 and increased expression of the gene, consistent with the idea that the proteasomal ATPases negatively regulate p53 function in a non-proteolytic fashion.

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Assembly and Function of the Proteasome

Saeki

Tanaka

2012

Methods in Molecular Biology

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Proteasome is a highly organized protease complex comprising a catalytic 20S core particle (CP) and two 19S regulatory particles (RP), which together form the 26S structure. The 26S proteasome is responsible for the degradation of most ubiquitylated proteins through a multistep process involving recognition of the polyubiquitin chain, unfolding of the substrate, and translocation of the substrate into the active site in the cavity of the CP. Recent studies have shed light on various aspects of the complex functions of the 26S proteasome. In addition, the recent identification of various proteasome-dedicated chaperones indicates that the assembly pathways of the RP and CP are multistep processes. In this review, we summarize recent advances in the understanding of the proteasome structure, function, and assembly.

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Physical and Functional Interactions of Monoubiquitylated Transactivators with the Proteasome

Cited by 34 publications

References 38 publications

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Non-proteolytic Regulation of p53-mediated Transcription through Destabilization of the Activator·Promoter Complex by the Proteasomal ATPases

Assembly and Function of the Proteasome

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