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complex(GO:"proteasome complex")

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Components

Entity

Name
proteasome complex
Namespace
go
Namespace Version
20180921
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

Appears in Networks 11

Chaperoning α7 neuronal nicotinic acetylcholine receptors v1.0.0

The Ubiquitin Proteasome System in Neurodegenerative Diseases: Sometimes the Chicken, Sometimes the Egg v1.0.0

Perilous journey: a tour of the ubiquitin–proteasome system v1.0.0

Alpha-synuclein oligomers: a new hope v1.0.0

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing v1.0.0

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

TAU and Interaction Partners v1.2.5

TAU Interactions Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease v1.0.0

Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection v1.0.0

In-Edges 40

a(CHEBI:"Congo Red") increases act(complex(GO:"proteasome complex")) View Subject | View Object

In a parallel experiment using a cell culture model, Congo red was found to increase proteasomal activity in cells expressing a polyglutamine protein but not in cells expressing a control protein (Sanchez et al., 2003). PubMed:14556719

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

However, Abeta has been demonstrated to reduce proteasome activity in reticulocyte lysates (Gregori et al., 1995), suggesting that increased levels of the peptide could underlie the reduction in UPS function observed in the AD brain. PubMed:14556719

Appears in Networks:
Annotations
MeSH
Reticulocytes

a(CHEBI:lactacystin) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003). PubMed:14556719

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

a(HBP:"paired helical filaments") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

They present evidence that paired helical filaments obtained from AD brain or generated in vitro can inhibit proteasome function and that in AD brain tissue these filaments coimmunoprecipitate with the proteasome (Keck et al., 2003). PubMed:14556719

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"protein K48-linked ubiquitination") increases act(complex(GO:"proteasome complex")) View Subject | View Object

The degradation signal that is recognized by the 26S proteasome complex is made of a Lys48 polyubiquitin chain. PubMed:14556719

Appears in Networks:

bp(GO:"protein K63-linked ubiquitination") increases act(complex(GO:"proteasome complex")) View Subject | View Object

Conjugation to other Lys residues, Lys63 for example, serves nonproteolytic functions of the system, such as activation of transcription PubMed:14556719

Appears in Networks:

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

The proteasome activity in the mammalian brain decreases with increasing age (Keller et al., 2002), suggesting that the aged brain is less able to handle the aberrantly folded Abeta PubMed:14556719

Appears in Networks:
Annotations
MeSH
Brain

p(HGNC:PRKN) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment PubMed:14556719

Appears in Networks:

complex(a(HBP:"alpha-synuclein aggregates"), p(HGNC:PSMC4)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

An important finding, however, in that respect is that aggregated and even monomeric alphaSYN bind to the S6' proteasome subunit and inhibit proteasomal function (Snyder et al., 2003). PubMed:14556719

Appears in Networks:

p(HGNC:ATXN3, frag("?")) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Concomitantly, it reduced the inhibition of the proteasome and the activation of caspase 12 that are induced by accumulation of the polyglutamine-containing fragment PubMed:14556719

Appears in Networks:

p(HGNC:HTT) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

In a cell culture model, they overexpressed mutant Huntingtin and observed proteasomal inhibition accompanied by cell cycle arrest PubMed:14556719

Appears in Networks:

complex(p(HGNC:PSMC4), p(HGNC:SNCA)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

An important finding, however, in that respect is that aggregated and even monomeric alphaSYN bind to the S6' proteasome subunit and inhibit proteasomal function (Snyder et al., 2003). PubMed:14556719

Appears in Networks:

p(HGNC:SOD1, var("?")) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

They found that the proteasome catalytic activity was decreased in neuroblastoma cells following 1 week of expression of a mutant SOD1 gene. PubMed:14556719

Appears in Networks:

p(HGNC:SOD1, var("?")) increases act(complex(GO:"proteasome complex")) View Subject | View Object

In the other model, the expression of mutant SOD1 alone was sufficient to induce oxidative stress, giving rise to increased proteasome activity, possibly due to the need to remove oxidatively damaged proteins (Hyun et al., 2003). PubMed:14556719

Appears in Networks:

a(HBP:HBP00093) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

This can be inhibited by a-syn oligomers: oligomers were shown to inhibit proteasomal activity, which was blocked by addition of antibodies that neutralized the interaction [87]. PubMed:28803412

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Endoplasmic Reticulum

a(HBP:HBP00006) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:HBP00016) decreases complex(GO:"proteasome complex") View Subject | View Object

Sixth, aggregates and mutant forms of α-synuclein disrupt the proteasome in dopaminergic neurons. PubMed:30116051

Appears in Networks:
Annotations
MeSH
Dopaminergic Neurons
MeSH
Parkinson Disease

a(PUBCHEM:3086599) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 . PubMed:30116051

Appears in Networks:

p(HGNC:MAPT, var("?")) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493

Appears in Networks:

act(complex(GO:"proteasome complex")) isA complex(GO:"proteasome complex") View Subject | View Object

Appears in Networks:

p(HGNC:BAG1) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

a(CHEBI:rolipram) increases act(complex(GO:"proteasome complex")) View Subject | View Object

Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin PubMed:26692334

Appears in Networks:

a(HBP:"O-GlcNAcylation") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809

Appears in Networks:

g(HGNC:OGT) positiveCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809

Appears in Networks:

act(p(FPLX:PKA)) positiveCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334

Appears in Networks:

act(p(HGNC:USP14)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. PubMed:26041011

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

For instance, phosphorylated insoluble tau proteins dampen 26S proteasome activity, while activation of the UPS attenuates tauopathy [27] PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) association complex(GO:"proteasome complex") View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Parahippocampal Gyrus
MeSH
Temporal Lobe

a(HBP:"Tau aggregates") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

In vitro experiments further showed that aggregated (recombinant) tau—but not nonaggregated (monomeric) tau—can inhibit the proteasome activity. PubMed:22908190

Appears in Networks:

a(HBP:"paired helical filaments") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190

Appears in Networks:

a(HBP:AβOs) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Moreover, soluble Ab oligomers themselves can inhibit proteasomal activity (Tseng et al. 2008). PubMed:22908190

Appears in Networks:

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:aging) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Parahippocampal Gyrus
MeSH
Parietal Lobe
MeSH
Temporal Lobe
MeSH
Alzheimer Disease

complex(a(GO:"proteasome regulatory particle"), a(HBP:"paired helical filaments")) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

Based on these various findings, it has been speculated that small aggregates of PHFs may bind to the cap portion of the 26S proteasome and inhibit its activity PubMed:22908190

Appears in Networks:

complex(a(GO:"proteasome regulatory particle"), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:autophagy) negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136

Appears in Networks:

Out-Edges 42

complex(GO:"proteasome complex") regulates p(FPLX:CHRN) View Subject | View Object

Regulation of receptor subunits by the proteasome, the large pro- tein complex that proteolytically degrades unneeded proteins, has also been demonstrated [113,114]. PubMed:22040696

Appears in Networks:

complex(GO:"proteasome complex") increases bp(GO:"modulation of chemical synaptic transmission") View Subject | View Object

Furthermore, the proteasome in- directly regulates synaptic transmission mediated by AChRs via regu- lation of RIC-3 [113]. PubMed:22040696

Appears in Networks:

complex(GO:"proteasome complex") regulates p(HGNC:RIC3) View Subject | View Object

Furthermore, the proteasome in- directly regulates synaptic transmission mediated by AChRs via regu- lation of RIC-3 [113]. PubMed:22040696

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(GO:"protein K48-linked ubiquitination"))) View Subject | View Object

Degradation of polyubiquitinated substrates is carried out by a large protease complex, the 26S proteasome that does not generally recognize nonmodified substrates PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(GO:"protein K63-linked ubiquitination"))) View Subject | View Object

Degradation of polyubiquitinated substrates is carried out by a large protease complex, the 26S proteasome that does not generally recognize nonmodified substrates PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") increases deg(complex(p(HGNC:OAZ1), p(HGNC:ODC1))) View Subject | View Object

In one established and exceptional case, however that of the polyamine synthesizing enzyme ornithine decarboxylase (ODC), the proteasome recognizes and degrades the substrate following its association with another protein, antizyme, without prior ubiquitination PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") increases a(CHEBI:peptide) View Subject | View Object

The proteasome is a large, multicatalytic protease that degrades polyubiquitinated proteins to small peptides PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") hasComponent p(HBP:"20 S Proteasome") View Subject | View Object

Appears in Networks:

complex(GO:"proteasome complex") hasComponent complex(GO:"proteasome regulatory particle") View Subject | View Object

Appears in Networks:

complex(GO:"proteasome complex") regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The UPS can be regulated at the level of ubiquitination or at the level of proteasome activity PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003). PubMed:14556719

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

The proteasome activity in the mammalian brain decreases with increasing age (Keller et al., 2002), suggesting that the aged brain is less able to handle the aberrantly folded Abeta PubMed:14556719

Appears in Networks:
Annotations
MeSH
Brain

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:SOD1, var("?")) View Subject | View Object

They found that the proteasome catalytic activity was decreased in neuroblastoma cells following 1 week of expression of a mutant SOD1 gene. PubMed:14556719

Appears in Networks:

act(complex(GO:"proteasome complex")) decreases bp(GO:autophagy) View Subject | View Object

Neuronal autophagy has been found to occur following chronic, low-grade proteasomal inhibition in cultured neuroblastoma cells (Ding et al., 2003) and may reflect activation of the lysosomal system as cells try to protect themselves during stress (Larsen and Sulzer, 2002). PubMed:14556719

Appears in Networks:
Annotations
MeSH
Neurons

act(complex(GO:"proteasome complex")) decreases p(HGNC:HTT, frag("?")) View Subject | View Object

Lunkes and colleagues demonstrated that truncated Huntingtin, which has undergone proteolytic cleavage in the cytoplasm, accumulates more rapidly if the proteasome is pharmacologically inhibited (Lunkes et al., 2002). PubMed:14556719

Appears in Networks:

complex(GO:"proteasome complex") regulates complex(a(MESH:Proteins), a(MESH:Ubiquitin)) View Subject | View Object

This observation suggests that chain binding and cleavage from the protein substrate are tightly coordinated by the proteasome, and may help to prevent situations such as premature chain cleavage by Rpn11, which could result in the release of the substrate before it becomes actively engaged to the proteasome. PubMed:24457024

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

Both aggregates and mutant forms of tau likewise block the proteasome, and its ability to degrade hyper- phosphorylated and oligomeric tau is reduced compared with its ability to degrade physiological tau 3,55,68 . PubMed:30116051

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

An additional “knot” of tau being entangled in epigenetic landscape of neurodegeneration comes from the finding that by acting as a HDAC6 inhibitor, tau is being indirectly involved in both (dys)regulation of transcriptional activity and impairment of autophagic clearance by the ubiquitin proteasome system [81,82]. PubMed:26751493

Appears in Networks:

act(complex(GO:"proteasome complex")) increases deg(p(HGNC:MAPT)) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

act(complex(GO:"proteasome complex")) isA complex(GO:"proteasome complex") View Subject | View Object

Appears in Networks:

act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:BAG1) View Subject | View Object

We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein.RNA-me- diated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. PubMed:17954934

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
HEK293
MeSH
Hippocampus

act(complex(GO:"proteasome complex")) negativeCorrelation a(HBP:"O-GlcNAcylation") View Subject | View Object

It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809

Appears in Networks:

act(complex(GO:"proteasome complex")) positiveCorrelation g(HGNC:OGT) View Subject | View Object

It has been reported that the proteasomal machinery is modified by O-GlcNAcylation [53,126] and that after modification by OGT, the proteasome is inhibited [53]. Intriguingly, it has been proposed that a genetic impairment in the OGA gene results in proteasomal dysfunction through a lack of hydrolysis of the inhibitory O-GlcNAc residues of the 19S regulatory cap. Indeed, the OGA gene is located in the 10q locus [127,128], a chromosomal region frequently mutated in AD. The impairment of OGA in AD and the subsequent static OGlcNAcylation of the proteasome may explain why the latter fails to degrade neuronal aggregates. In addition, it has been reported that OGlcNAcylation reduces the sensitivity of intracellular proteins to proteasomal degradation by directly modifying them [43,129,130]. The two phenomena could thus act synergistically: a protein could escape degradation by means of its own O-GlcNAcylation and by the inhibitory effect of glycosylation on the proteasome, leading to a considerable decrease in the turnover of proteins that in turn may aggregate and cause neuronal death. PubMed:19732809

Appears in Networks:

act(complex(GO:"proteasome complex")) decreases a(HBP:"Tau aggregates") View Subject | View Object

We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. PubMed:26041011

Appears in Networks:

act(complex(GO:"proteasome complex")) positiveCorrelation act(p(FPLX:PKA)) View Subject | View Object

PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(HGNC:SNCA)) View Subject | View Object

Since the initial finding of proteasome-dependent degradation of α-synuclein [58], significant efforts have been made to clarify the modes of α-synuclein metabolism PubMed:29758300

Appears in Networks:

complex(GO:"proteasome complex") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

The proteasome selectively degrades normal proteins (mainly those with short half-lives) and abnormal proteins, which are earmarked for elimination by a process involving their conjugation to ubiquitin (Ub; Goldberg 2003). PubMed:22908190

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(MESH:Proteins, pmod(UbK48))) View Subject | View Object

Proteins tagged with chains of four or more K48-linked multiubiquitins provide the strongest signal for degradation by the 26S proteasome, because a chain of at least four Ub moieties is required for substrate recognition by the 26S proteasome complex. PubMed:22908190

Appears in Networks:

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

AD is the most common of numerous age-associated brain diseases, and the activity of brain proteasomes appears to decline with age (Keller et al. 2002). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:aging) View Subject | View Object

Beyond an age-related reduction (Keller et al. 2002), proteasome activities decrease in AD in a brain region–specific manner, particularly in hippocampus, parahippocampal gyrus, superior and middle temporal gyri, and the inferior parietal lobule (Keller et al. 2000), areas that are especially critical for long-term memory formation. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Parahippocampal Gyrus
MeSH
Parietal Lobe
MeSH
Temporal Lobe
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation a(HBP:"paired helical filaments") View Subject | View Object

PHF have been associated with inhibition of the activity of the proteasome in a brain region–specific manner (Keller et al. 2000). PubMed:22908190

Appears in Networks:

act(complex(GO:"proteasome complex")) negativeCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

That is, in areas where NFTs formed abundantly, including hippocampus and parahippocampal gyrus and superior and middle temporal gyri, proteasome activity (as assessed by chymortrypsinlike and postglutamyl peptidases) appeared to be most affected, whereas occipital gyri and cerebellum, which often have few or no NFTs, were least affected (Keller et al. 2000). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Parahippocampal Gyrus
MeSH
Temporal Lobe

act(complex(GO:"proteasome complex")) negativeCorrelation complex(a(GO:"proteasome regulatory particle"), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Another study of AD brain tissues showed that hyperphosphorylated tau was bound to the proteasome, presumably to the 19S cap portion, and the more tau that was bound, the more that proteasomes appeared to be inhibited (Keck et al. 2003). PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(GO:"proteasome complex") increases deg(p(FPLX:PKA, pmod(Ub))) View Subject | View Object

During the induction of long-term facilitation in the snail, the regulatory subunit of cAMP-dependent protein kinase (PKA) is ubiquitinated and degraded by the proteasome, generating persistently activated PKA (Hegde et al. 1993). PubMed:22908190

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

It has been reported that tau is degraded by several major cellular degradation systems, including calpain, caspases, lysosomes, and proteasomes. PubMed:22908190

Appears in Networks:

complex(GO:"proteasome complex") increases deg(p(HGNC:MAPT)) View Subject | View Object

As regards the proteasome, both the ATP-dependent 26S proteasome and the ATP-independent 20S proteasome have been reported to degrade normal, soluble tau (Cardozo et al. 2002; Zhang et al. 2005). PubMed:22908190

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act(complex(GO:"proteasome complex")) negativeCorrelation p(HGNC:MAPT) View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

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Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(complex(GO:"proteasome complex")) decreases path(HBP:Neurodegeneration) View Subject | View Object

There have been fewer efforts to manipulate UPS function for therapeutic benefit in neurodegenerative disease, but it was recently shown that use of a proteasome activator enhanced survival in an in vitro model of Huntington’s disease [58], suggesting that augmenting other routes of protein degradation may also provide neuroprotection. PubMed:18930136

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Annotations
MeSH
Huntington Disease

act(complex(GO:"proteasome complex")) negativeCorrelation bp(GO:autophagy) View Subject | View Object

Similar induction of autophagy is observed in response to genetic impairment of the proteasome in Drosophila [50]. PubMed:18930136

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act(complex(GO:"proteasome complex")) decreases p(HGNC:SQSTM1) View Subject | View Object

Cellular stresses such as polyQ expression, proteasome impairment, oxidative stress, and increased misfolded protein burden activate transcription and translation of p62, suggesting that it functions broadly in stress situations [83,84] PubMed:18930136

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.