Phosphorylation and Ubiquitination of the 26S Proteasome Complex

Etlinger, Joseph D.; Li, Simon X.; Guo, Gary; Li, Nelson

doi:10.1159/000468690

Cited by 16 publications

(9 citation statements)

References 8 publications

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“…Additionally, proteins were found that have roles in protein trafficking/localization, protein structure, and the immune system, consistent with previously reported roles for ubiquitination11–14. Many ubiquitin-conjugating enzymes, ubiquitin ligases, and 26S proteasome regulatory subunits are ubiquitinated, consistent with previous studies that many proteins involved in proteasome degradation pathways are ubiquitinated15, 16. Some proteins found to be ubiquitinated extend findings regarding the role of ubiquitination in certain cellular processes.…”

supporting

confidence: 89%

Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling

2010

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Protein ubiquitination is a post-translational modification (PTM) that regulates various aspects of protein function by different mechanisms. Global profiling of PTMs usually relies on purification and sequencing of PTM-containing peptides from proteolytic digests. Characterization of ubiquitination has lagged behind that of smaller PTMs, such as phosphorylation and acetylation, largely because of the difficulty of isolating and identifying peptides derived from the ubiquitinated portion of proteins. To address this issue, we have generated a monoclonal antibody that can enrich for peptides containing lysine residues modified by diglycine, an adduct left at sites of ubiquitination after trypsin digestion. We use mass spectrometry to identify 374 diglycine-modified lysines on 236 ubiquitinated proteins from HEK293 cells, including 80 proteins containing multiple sites of ubiquitination. Seventy-two percent of these proteins and 92% of the ubiquitination sites do not appear to have been reported previously. Ubiquitin remnant profiling of the multi-ubiquitinated proteins proliferating cell nuclear antigen (PCNA) and tubulin α-1A reveals differential regulation of ubiquitination at specific sites by microtubule inhibitors, demonstrating the effectiveness of our method to characterize the dynamics of lysine ubiquitination.

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supporting

confidence: 89%

Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling

2010

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“…The biological function of the 11 S regulator is not fully understood but it is presumed to be related to the proteasomal role in antigen processing. 20 Other speculations involve the 11 S regulator as an adapter molecule between the 20 S proteasome and chaperons, an idea that would be consistent with the report that some proteasome preparations contain chaperons. 21 When the other complex, the 19 S regulator, binds to both ends of the 20 S proteasome, a new protease is formed: the 26 S proteasome.…”

Section: The Proteasome: Function Regulation and Distributionsupporting

confidence: 54%

“…The 11 S regulator is a heptameric or hexameric structure that binds to the outer ring of the 20 S proteasome and modulates its activity. The biological function of the 11 S regulator is not fully understood but it is presumed to be related to the proteasomal role in antigen processing 20 . Other speculations involve the 11 S regulator as an adapter molecule between the 20 S proteasome and chaperons, an idea that would be consistent with the report that some proteasome preparations contain chaperons 21 …”

Section: The Proteasome: Function Regulation and Distributionmentioning

confidence: 65%

The proteasome and its function in the ageing process

Stolzing

Grune

2001

Clinical and Experimental Dermatology

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The ageing process is characterized by a progressive loss of function and a decline in the functional capacities of the organism, leading to death. The nature of the processes involved in loss of functions is not well understood. A number of theories have been proposed, including a hypothesis that emphasizes the role of reactive oxygen species as a fundamental causal factor in the ageing process; among other things, oxidative damage to proteins through reactive oxygen species plays a key role in the ageing process. Oxidative modification of proteins generally causes them to become dysfunctional, and normally to undergo preferential degradation. Within the cell the main proteolytic machinery involved in the degradation of oxidized proteins is the proteasomal system, consisting of a multicatalytic protease complex--the proteasome--and numerous regulatory factors. The proteasome is a highly conserved structure that is distributed in the cytosol, nucleus and endoplasmatic reticulum of mammalian cells. As the proteasome itself is also exposed to oxidative stress during the ageing process several studies were carried out to investigate the role and the activity of the proteasomal system during ageing. This review will describe current knowledge of the activity of the protesomal system and its possible involvement in the ageing process.

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“…Several subunits of the proteasome have been reported to be phosphorylated in vivo [43, 44], however, relatively few studies have addressed how phosphorylation may regulate proteasome function. Phosphorylation might regulate proteasome subunit assembly, disassembly, or distinct proteasome activities, such as peptidase activity, ATPase activity, ubiquitin binding, and/or deubiquitinating activities.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation

et al. 2017

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The ubiquitin proteasome system (UPS) is a highly conserved and tightly regulated biochemical pathway that degrades the majority of proteins in eukaryotic cells. Importantly, the UPS is responsible for counteracting altered protein homeostasis induced by a variety of proteotoxic stresses. We previously reported that Rpt6, the ATPase subunit of the 19S regulatory particle (RP) of the 26S proteasome, is phosphorylated in mammalian neurons at serine 120 in response to neuronal activity. Furthermore, we found that Rpt6 S120 phosphorylation, which regulates the activity and distribution of proteasomes in neurons, is relevant for proteasome-dependent synaptic remodeling and function. To better understand the role of proteasome phosphorylation, we have constructed models of altered Rpt6 phosphorylation in S. cerevisiae by introducing chromosomal point mutations that prevent or mimic phosphorylation at the conserved serine (S119). We find that mutants which prevent Rpt6 phosphorylation at this site (rpt6-S119A), had increased susceptibility to proteotoxic stress, displayed abnormal morphology and had reduced proteasome activity. Since impaired proteasome function has been linked to the aggregation of toxic proteins including the Huntington’s disease (HD) related huntingtin (Htt) protein with expanded polyglutamine repeats, we evaluated the extent of Htt aggregation in our phospho-dead (rpt6-S119A) and phospho-mimetic (rpt6-S119D) mutants. We showed Htt103Q aggregate size to be significantly larger in rpt6-S119A mutants compared to wild-type or rpt6-S119D strains. Furthermore, we observed that phosphorylation of endogenous Rpt6 at S119 is increased in response to various stress conditions. Together, these data suggest that Rpt6 phosphorylation at S119 may play an important function in proteasome-dependent relief of proteotoxic stress that can be critical in protein aggregation pathologies.

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Phosphorylation and Ubiquitination of the 26S Proteasome Complex

Cited by 16 publications

References 8 publications

Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling

Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling

The proteasome and its function in the ageing process

Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation

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