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Entity

Name
proteasome-mediated ubiquitin-dependent protein catabolic process
Namespace
go
Namespace Version
20180921
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/go-names.belns

Appears in Networks 9

In-Edges 36

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

For example, upregulation of the pathway is observed during massive degradation of skeletal muscle proteins that occurs under normal fasting but also under pathological conditions such as cancer-induced cachexia, severe sepsis, metabolic acidosis, or following denervation PubMed:14556719

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

Lindquist and colleagues proposed that inhibition of UPS, which can be caused by ageing or following a pharmacological treatment, can lead to accumulation of PrPc in the cytoplasm where it is spontaneously converted into a PrPsc-like species because it is not rapidly degraded by the UPS (Hooper, 2003; Ma and Lindquist,2002;Ma et al., 2002). PubMed:14556719

p(HGNC:HTT, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Another study has also demonstrated that UPS inhibition is only revealed under conditions of increased stress in cells expressing mutant Huntingtin (Ding et al., 2002) PubMed:14556719

p(HGNC:RNF19A) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Similarly, overexpression of the putative SOD1 E3 ligase dorfin can inhibit cell death induced by the mutant protein (Niwa et al., 2002), presumably by promoting its removal via the UPS. PubMed:14556719

p(HGNC:UCHL1, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The simple explanation is that the mutation leads to a shortage in free ubiquitin that should have been recycled from conjugates, which results in general impairment of the function of the UPS. PubMed:14556719

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

path(MESH:"Prion Diseases") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Recent work has highlighted a novel possible role for failure of the UPS in initiating prion disease, which can explain the cause of some cases of sporadic prion disease. PubMed:14556719

path(MESH:"Prion Diseases") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The model proposed by Lindquist and collaborators is important as it identifies malfunction of UPS as a potentially important player in prion pathogenesis PubMed:14556719

p(FPLX:mTORC1) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Finally, mirroring its inhibitory influence on the ALN, mTORC1 suppresses the UPS by impeding the formation and assembly of proteasomal subunits. PubMed:30116051

p(HGNC:LRRK2, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

In addition, CMA is disrupted by sev- eral genetic mutations occurring in PD, including muta- tions in LRRK2 (REFS2,3,45–47,55,69,80) . PubMed:30116051

p(HGNC:MAPT) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The UPS and CMA are disrupted by neurotoxic proteins like Aβ42 and tau, hence, their early and preventive reinforcement prior to Aβ42 and tau accumulation may be critical. PubMed:30116051

p(HGNC:PRKN, var("?")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Furthermore, mutations in the gene encoding parkin and several other genes are linked to reduced UPS activity 2,56,69,79,80 . PubMed:30116051

a(HBP:"Tau aggregates") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

deg(p(HGNC:MAPT)) association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

a(HBP:"Tau aggregates") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

p(HGNC:MAPT, var("p.Ala152Thr")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers. PubMed:29758300

path(HBP:Neurodegeneration) negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Impairment in the UPS is cardinal to the development of neurodegeneration, in part because of its reciprocal interplay with protein aggregation PubMed:29758300

bp(GO:"regulation of synaptic plasticity") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity. PubMed:22908190

p(HBP:"UBB+1") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Indeed, transgenic mice expressing UBB+1 have an impaired UPS and show contextual memory deficits in both water maze and fear conditioning paradigms, without specific neuropathological findings (Fischer et al. 2009). PubMed:22908190

p(HBP:"UBB+1", pmod(UbPoly)) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

The resulting polyubiquitinated UBB+1 cannot be degraded by proteasomes and impairs the UPS (Lam et al. 2000), which may induce neurotoxicity. PubMed:22908190

p(HGNC:BAG1) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

BAG1 targets proteins for degradation by the UPS, whereas BAG3 mediates degradation by macroautophagy. PubMed:23746257

p(HGNC:HDAC6) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136

p(HGNC:SQSTM1) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136

p(HGNC:SQSTM1) increases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Thus, it has been suggested that p62 provides a key link between autophagy and the UPS by facilitating autophagic degradation of ubiquitinated proteins. PubMed:18930136

p(HGNC:WDFY3) regulates bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Although the mechanism whereby autophagy and UPS function are coordinated is little understood, several regulators have emerged as important players in mediating this crosstalk, including histone deacetylase 6 (HDAC6) [50,64,75], p62/sequestosome 1 (p62) [76], and the FYVE-domain containing protein Alfy [77]; notably, these proteins have all been found to regulate or be essential for aggresome formation PubMed:18930136

path(HBP:Neurodegeneration) negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Indeed, experimental evidence indicates that neurodegeneration is frequently associated with impaired UPS function, although whether this is a cause or consequence of neurodegeneration is a contested issue, as is reviewed elsewhere in this special issue PubMed:18930136

Out-Edges 43

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:PARK7)) View Subject | View Object

Miller and colleagues (Miller et al., 2003) have recently shown that this mutation destabilizes DJ-1 via promotion of its rapid, UPS-mediated degradation PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Prion Diseases") View Subject | View Object

Recent work has highlighted a novel possible role for failure of the UPS in initiating prion disease, which can explain the cause of some cases of sporadic prion disease. PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Prion Diseases") View Subject | View Object

The model proposed by Lindquist and collaborators is important as it identifies malfunction of UPS as a potentially important player in prion pathogenesis PubMed:14556719

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

Lindquist and colleagues proposed that inhibition of UPS, which can be caused by ageing or following a pharmacological treatment, can lead to accumulation of PrPc in the cytoplasm where it is spontaneously converted into a PrPsc-like species because it is not rapidly degraded by the UPS (Hooper, 2003; Ma and Lindquist,2002;Ma et al., 2002). PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:PRNP)) View Subject | View Object

Once in the cytoplasm, the PrPc would be efficiently degraded by the UPS via the ERAD pathway, but this does not occur in the presence of the proteasome inhibitors PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Similarly, overexpression of the putative SOD1 E3 ligase dorfin can inhibit cell death induced by the mutant protein (Niwa et al., 2002), presumably by promoting its removal via the UPS. PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SOD1, var("?"))) View Subject | View Object

Urushitani and coworkers (Urushitani et al., 2002) showed that mutant SOD1 is degraded by the UPS in cultured cells and that oxidative damage increases the degree of ubiquitination of mutant but not of wild-type SOD1. PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:HTT, frag("?"))) View Subject | View Object

This indicates that the truncated fragments are normally processed via the UPS, and therefore the disposal of fragments of mutant proteins will be impaired. PubMed:14556719

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:MAPT)) View Subject | View Object

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 . PubMed:30116051

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases bp(GO:"regulation of synaptic plasticity") View Subject | View Object

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 . PubMed:30116051

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases bp(GO:"dendrite development") View Subject | View Object

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 . PubMed:30116051

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

Interestingly, the UPS is important for elimination of tau and other neurotoxic proteins in post synaptic dendritic compartments (a key site of spreading), where it plays a more general role favouring synaptic plasticity, den- dritogenesis and memory formation 49,52 . PubMed:30116051

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association deg(p(HGNC:MAPT)) View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association a(HBP:"Tau aggregates") View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") regulates deg(a(MESH:Proteins)) View Subject | View Object

Under physiological conditions, UPS, located in the cytosol and the nucleus in eukaryotic cells, as a major intracellular short-lived protein degradation system (Schwartz and Ciechanover 2009), mediates the clearance of misfolded or other abnormally modified proteins with the help of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin ligase (E3), and the 26S proteasome for the sake of preventing the accumulation of toxic substances (Shang and Taylor 2011) PubMed:29626319

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ clearance can be achieved through UPS and ALS, and extracellular Aβ is degraded by glial phagocytosis, such as microglia, astrocytes, and proteases from neurons and astrocytes (Fig. 2) PubMed:29626319

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(HBP:Neurodegeneration) View Subject | View Object

Impairment in the UPS is cardinal to the development of neurodegeneration, in part because of its reciprocal interplay with protein aggregation PubMed:29758300

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") decreases path(MESH:Tauopathies) View Subject | View Object

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

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association a(HBP:"Tau aggregates") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SNCA)) View Subject | View Object

These experimental differences may be attributed to the intricate interplay between the UPS and autophagy, as α-synuclein is degraded by both proteolytic systems [62,63]. PubMed:29758300

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(MESH:Proteins, pmod(Ub))) View Subject | View Object

It has recently become appreciated that ubiquitination of proteins by covalent modification tags them for elimination not only through the proteasome (the ubiquitin–proteasome system or UPS) but also through the lysosomal system. PubMed:22908190

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity. PubMed:22908190

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:ARC)) View Subject | View Object

This and numerous related findings suggest that degradation of certain critical proteins by the UPS is required during long-term memory formation. One of these proteins is arc, a negative regulator of synaptic strength that promotes the internalization of AMPA receptors and is degraded via the E3 ligase, UBE3A (Greer et al. 2010). PubMed:22908190

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases bp(GO:"long-term memory") View Subject | View Object

This and numerous related findings suggest that degradation of certain critical proteins by the UPS is required during long-term memory formation. One of these proteins is arc, a negative regulator of synaptic strength that promotes the internalization of AMPA receptors and is degraded via the E3 ligase, UBE3A (Greer et al. 2010). PubMed:22908190

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

UPS-mediated catabolism is also essential to mainten amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins [1,2,7]. PubMed:18930136

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

UPS-mediated catabolism is also essential to mainten amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins [1,2,7]. PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases rxn(reactants(a(MESH:Proteins)), products(a(CHEBI:oligopeptide))) View Subject | View Object

This role in recycling is complementary to that of the UPS, which degrades proteins to generate oligopeptides that are subsequently degraded into amino acids while replenishing the cell’s supply of free ubiquitin. PubMed:18930136

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

This role in recycling is complementary to that of the UPS, which degrades proteins to generate oligopeptides that are subsequently degraded into amino acids while replenishing the cell’s supply of free ubiquitin. PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(HBP:Neurodegeneration) View Subject | View Object

Indeed, experimental evidence indicates that neurodegeneration is frequently associated with impaired UPS function, although whether this is a cause or consequence of neurodegeneration is a contested issue, as is reviewed elsewhere in this special issue PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SNCA)) View Subject | View Object

In the case of α-synuclein, for example, Webb et al. concluded that soluble forms of the disease protein are efficiently degraded by the UPS, while aggregated or oligomeric α-synuclein require autophagy for clearance [26]. PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SNCA)) View Subject | View Object

The neuronal protein α-synuclein, for example, can be degraded by the UPS, macroautophagy and chaperone-mediated autophagy [26,29]. PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") decreases tloc(p(HGNC:WDFY3), fromLoc(GO:nucleus), toLoc(GO:cytoplasm)) View Subject | View Object

In cells that are exposed to stressors such as starvation or UPS inhibition, Alfy relocalizes from the nuclear envelope to filamentous cytoplasmic structures that are near autophagic membranes and ubiquitinated protein inclusions, as well as within autophagosomes [77]. PubMed:18930136

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:MAPT)) View Subject | View Object

The two major pathways for protein degradation in cells are through the ubiquitin-proteasome system and the autophagy-lysosome system [10, 11], both of which have been implicated in tau degradation in AD [12]. PubMed:25374103

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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.