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Entity

Name
Proteasome
Namespace
FPLX
Namespace Version
20180917
Namespace URL
https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns

Appears in Networks 6

In-Edges 18

a(CHEBI:"amyloid-beta") decreases act(p(FPLX:Proteasome)) View Subject | View Object

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74). PubMed:25784053

a(PUBCHEM:675434) causesNoChange p(FPLX:Proteasome) View Subject | View Object

Treatment with IU1 reduced the levels of Tau, TDP-43, and ataxin-3 in MEFs in a USP14-dependent manner and independently of changes in proteasome levels or composition (147). PubMed:25784053

Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

p(HGNC:USP14) decreases act(p(FPLX:Proteasome)) View Subject | View Object

The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some; PubMed:25784053

Annotations
Experimental Factor Ontology (EFO)
MEF cell line
Cell Ontology (CL)
motor neuron

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:Proteasome)) View Subject | View Object

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74). PubMed:25784053

a(PUBCHEM:675434) increases act(p(FPLX:Proteasome)) View Subject | View Object

In a cell-based assay, IU1 treatment increased proteasomal activity to result in accelerated degradation rates of tau and oxidatively damaged proteins. PubMed:23528736

a(CHEBI:epoxomicin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(CHEBI:lactacystin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(CHEBI:leupeptin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005). PubMed:23528736

a(HBP:"amyloid-beta oligomers") decreases act(p(FPLX:Proteasome)) View Subject | View Object

Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008). PubMed:23528736

a(HP:"Neurofibrillary tangles") decreases act(p(FPLX:Proteasome)) View Subject | View Object

PHF-tau isolated from human AD brains in the soluble state was not degraded by the proteasome but instead functioned as an inhibitor of its activity (Keck et al., 2003). PubMed:23528736

p(HBP:"UBB+1") decreases act(p(FPLX:Proteasome)) View Subject | View Object

UBB+ 1-capped polyUb chains are resistant to deubiquitination and inhibit proteasomal activity, which may mediate neurodegeneration through mitochondrial stress and p53 activation in neurites (Tan et al., 2007). PubMed:23528736

bp(MESH:Aging) decreases act(p(FPLX:Proteasome)) View Subject | View Object

The activity of both the proteasome, which is the main mechanism of protein degradation (Rock et al., 1994; Conconi et al., 1996), and chaperone-mediated autophagy (CMA; Cuervo and Dice, 2000b) is significantly impaired with aging and is especially pronounced in post-mitotic cells, such as neurons, potentially resulting in neurodegenerative disease (Terman, 2001). PubMed:29311797

bp(MESH:Aging) decreases act(p(FPLX:Proteasome)) View Subject | View Object

In addition to the problems faced with an overwhelmed chaperone network, the proteolytic activity of the proteasome also declines with aging, and in fact Hsp90 has been shown to protect the proteasome from age-related, oxidative-dependent decline (Conconi and Friguet, 1997). PubMed:29311797

p(FPLX:HSP90) increases act(p(FPLX:Proteasome)) View Subject | View Object

In addition to the problems faced with an overwhelmed chaperone network, the proteolytic activity of the proteasome also declines with aging, and in fact Hsp90 has been shown to protect the proteasome from age-related, oxidative-dependent decline (Conconi and Friguet, 1997). PubMed:29311797

a(CHEBI:epoxomicin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931

a(CHEBI:lactacystin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28]. PubMed:30145931

a(CHEBI:rolipram) increases act(p(FPLX:Proteasome)) View Subject | View Object

Treatment with rolipram (10 µM) on the neuritic side for 24 h (Fig. 5C) supressed missorting of MAPT down to 4.5±0.4% dendrites, far below the control level (20.5±5.6% dendrites) (Fig. 5D), thereby confirming the role of the proteasome in degrading dendritic MAPT. PubMed:30145931

Out-Edges 11

p(FPLX:Proteasome) increases bp(MESH:Proteolysis) View Subject | View Object

. Proteins can be degraded either individually or en masse by proteasomes (20) or lysosomes (21), respectively. PubMed:25784053

p(FPLX:Proteasome) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

As discussed above, one approach is to employ specialized molecular chaperone machines to release misfolded proteins from aggregates and direct them to the proteasome for degradation (19). PubMed:25784053

act(p(FPLX:Proteasome)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74). PubMed:25784053

p(FPLX:Proteasome) increases bp(GO:"protein catabolic process") View Subject | View Object

The PN branch of degradation includes the ubiquitin- proteasome system (UPS) and machinery of autophagy (23, 196–200). PubMed:23746257

p(FPLX:Proteasome) increases bp(GO:"protein unfolding") View Subject | View Object

Degradation via the UPS depends on pro- tein unfolding by the 26S proteasome (201) and generally requires that chaperones maintain target proteins in a nonaggregated state. PubMed:23746257

act(p(FPLX:Proteasome)) decreases path(HBP:neurotoxicity) View Subject | View Object

Our previous work showed that inhibition of either the proteasome or autophagy in primary neurons induces pronounced neurotoxicity [23,24], making it impossible to address this issue in conventional neuron cultures. PubMed:30145931

act(p(FPLX:Proteasome)) decreases p(HGNC:MAPT) View Subject | View Object

In controls, the fraction of MAPT-containing dendrites on the neuritic side was low (~14%), but local treatment with inhibitors of either autophagy (wortmannin [Fig. 3B], bafilomycin A 1 [Fig. S3A]) or the proteasome (epoxomicin [Fig. 3C], lactacystin [Fig. S3B]) caused a pronounced 4-to 5-fold increase of MAPT-containing dendrites (to levels of ~50-76%) (Fig. 3D). PubMed:30145931

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, loc(MESH:Dendrites))) View Subject | View Object

Treatment with rolipram (10 µM) on the neuritic side for 24 h (Fig. 5C) supressed missorting of MAPT down to 4.5±0.4% dendrites, far below the control level (20.5±5.6% dendrites) (Fig. 5D), thereby confirming the role of the proteasome in degrading dendritic MAPT. PubMed:30145931

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356))) View Subject | View Object

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site. PubMed:30145931

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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.