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PubMed: 25374103

Title
Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes.
Journal
Journal of Alzheimer's disease : JAD
Volume
44
Issue
None
Pages
937-47
Date
2015-01-01
Authors
Polydoro M | Saidi LJ | Kay KR | Sanchez L | Hyman BT | Mandelkow EM | Spires-Jones TL

Evidence 938e962280
JSON

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles.

a(HBP:"Tau aggregates") increases a(GO:"neurofibrillary tangle") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

complex(a(GO:microtubule), p(HGNC:MAPT)) decreases p(HGNC:MAPT, pmod(HBP:misfolded)) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

tloc(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) increases a(HBP:"Tau aggregates") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence 4802bc07d9
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Several publications suggest that molecular chaperones, e.g., heat shock protein 70 and 90 (Hsp70, Hsp90) play a fundamental role in the clearance of misfolded proteins including tau [12].

a(MESH:"HSP70 Heat-Shock Proteins") increases deg(p(HGNC:MAPT, pmod(HBP:misfolded))) View Subject | View Object

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p(FPLX:HSP90) increases deg(p(HGNC:MAPT, pmod(HBP:misfolded))) View Subject | View Object

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Evidence a0c99d20e6
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The overexpression of full-length tau in Chinese hamster ovary (CHO) cells [3], N2A cells [4], cultured retinal ganglion cells [4], NB2a/d1 cells [5] H4-cells [6], and primary cortical neuron cultures [6] led to an impairment of anterograde transport of a variety of kinesin cargos, including mitochondria

bp(GO:"anterograde axonal transport") negativeCorrelation p(HGNC:MAPT) View Subject | View Object

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p(HGNC:MAPT) negativeCorrelation bp(GO:"anterograde axonal transport") View Subject | View Object

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Evidence 56e1e98ca4
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This leads to accumulation of mitochondria in the cell body where they cluster near the microtubule center [6].

bp(GO:"anterograde axonal transport") decreases a(GO:microtubule) View Subject | View Object

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MeSH
Cell Body

Evidence 3a32acbde7
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Thies and Mandelkow [7] have shown previously that the co-expression of microtubule-associated protein/microtubule affinityregulating kinase 2 (MARK2) with tau can rescue these effects caused by tau overexpression in vitro.

bp(GO:"anterograde axonal transport") positiveCorrelation composite(p(HGNC:MAPT), p(HGNC:MARK2)) View Subject | View Object

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composite(p(HGNC:MAPT), p(HGNC:MARK2)) positiveCorrelation bp(GO:"anterograde axonal transport") View Subject | View Object

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Evidence c242423bba
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Misfolded tau proteins, like other natively unfolded molecules, can be detected and cleared by chaperone assisted mechanisms [13].

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT, pmod(HBP:misfolded))) View Subject | View Object

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Evidence 01ee96c454
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As expected, we observed a significant impairment of mitochondrial distribution with overexpression of all three tau constructs (p < 0.0001, Wilcoxon test for GFP control versus 4R-tau, GFP versus tauC3, and GFP versus K18ΔK280) (Fig. 5).

bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"Tau isoform F (441 aa)") View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"Tau C3") View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"4R tau", var("p.Lys280del")) View Subject | View Object

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p(HBP:"Tau C3") negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)") negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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p(HBP:"4R tau", var("p.Lys280del")) negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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Evidence b0a5736a73
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Taken together, these data indicate that tau-overexpression leads to abnormal mitochondrial trafficking that can be rescued by CHIP-co-expression

bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"Tau isoform F (441 aa)") View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"Tau C3") View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") negativeCorrelation p(HBP:"4R tau", var("p.Lys280del")) View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) View Subject | View Object

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p(HBP:"Tau C3") negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)") negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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p(HBP:"4R tau", var("p.Lys280del")) negativeCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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Evidence 2a56386d36
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CHIP co-expression led to a significant recovery in the area of mitochondria around the nucleus (19–26%).

bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) View Subject | View Object

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bp(GO:"mitochondrion transport along microtubule") positiveCorrelation composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) View Subject | View Object

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composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) positiveCorrelation bp(GO:"mitochondrion transport along microtubule") View Subject | View Object

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Evidence 68d6ab60e2
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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].

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

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MeSH
Alzheimer Disease

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

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MeSH
Alzheimer Disease

Evidence f610470df1
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The tau-protein is a natively soluble protein that plays a key role in the dynamics of microtubules

p(HGNC:MAPT) regulates act(a(GO:microtubule)) View Subject | View Object

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Evidence 5347afe0da
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Recent data suggest that a critical mediator of refolding or clearance of hyperphosphorylated tau is via the HSP70/HSP90 heat shock pathways in which a specific E3 ubiquitin ligase, CHIP (carboxy terminus Hsp70 interacting protein), can recognize and target for degradation abnormal but not normal tau molecules [14–16].

p(FPLX:HSP90) regulates deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

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p(HGNC:STUB1) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

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Evidence 5fff8a7741
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CHIP is also implicated in regulation of Caspase 3 activity

p(HGNC:STUB1) regulates act(p(HGNC:CASP3)) View Subject | View Object

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Evidence 9cc1f97745
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CHIP interacts more strongly with tauΔC than full-length tau [18], suggesting it is involved in caspase cleaved tau degradation

p(HGNC:STUB1) increases complex(p(HBP:"Tau C3"), p(HGNC:STUB1)) View Subject | View Object

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p(HGNC:STUB1) increases deg(p(HBP:"Tau C3")) View Subject | View Object

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Evidence 6556a5b0c7
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Dolan et al. [20] showed that CHIP interacts more strongly with tauC3 than full length tau.

p(HGNC:STUB1) increases complex(p(HBP:"Tau C3"), p(HGNC:STUB1)) View Subject | View Object

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p(HGNC:STUB1) increases complex(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) View Subject | View Object

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Evidence 88ee93c34a
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Recent data suggest that caspases are involved in the accumulation of tau pathology [10, 25, 26], and reductions in CHIP have been shown to cause caspase activation and increased caspase-cleaved tau levels [19].

p(HGNC:STUB1) negativeCorrelation p(HBP:"Tau C3") View Subject | View Object

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p(HGNC:STUB1) negativeCorrelation act(p(FPLX:Caspase)) View Subject | View Object

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p(HBP:"Tau C3") negativeCorrelation p(HGNC:STUB1) View Subject | View Object

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p(FPLX:Caspase) positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

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act(p(FPLX:Caspase)) negativeCorrelation p(HGNC:STUB1) View Subject | View Object

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path(MESH:Tauopathies) positiveCorrelation p(FPLX:Caspase) View Subject | View Object

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Evidence 3ddca5dbaa
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These results indicate that CHIP is involved in degradation of caspases and caspase-cleaved tau.

p(HGNC:STUB1) increases deg(p(HBP:"Tau C3")) View Subject | View Object

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p(HGNC:STUB1) increases deg(p(FPLX:Caspase)) View Subject | View Object

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Evidence a0757601ef
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Toxicity assays revealed that neither CHIP nor any of the tau constructs caused cell death compared to the control GFP vector (Supplementary Fig. 1).

p(HGNC:STUB1) causesNoChange bp(GO:"cell death") View Subject | View Object

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p(HBP:"Tau C3") causesNoChange bp(GO:"cell death") View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)") causesNoChange bp(GO:"cell death") View Subject | View Object

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p(HBP:"4R tau", var("p.Lys280del")) causesNoChange bp(GO:"cell death") View Subject | View Object

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Evidence d4d09adfc1
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The co-chaperone CHIP interacts with Hsp70/Hsp90 to bind unfolded and misfolded proteins

p(HGNC:STUB1) increases complex(p(FPLX:HSP90), p(HGNC:STUB1)) View Subject | View Object

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p(HGNC:STUB1) increases complex(a(MESH:"HSP70 Heat-Shock Proteins"), p(HGNC:STUB1)) View Subject | View Object

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complex(a(MESH:"HSP70 Heat-Shock Proteins"), p(HGNC:STUB1)) increases complex(a(MESH:"HSP70 Heat-Shock Proteins"), p(HGNC:STUB1), p(MESH:Proteins, pmod(HBP:misfolded))) View Subject | View Object

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complex(p(FPLX:HSP90), p(HGNC:STUB1)) increases complex(p(FPLX:HSP90), p(HGNC:STUB1), p(MESH:Proteins, pmod(HBP:misfolded))) View Subject | View Object

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Evidence 684c383cc2
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Either of these domains could be critical for degradation of tau since ubiquitination targets proteins for degradation and CHIP is known to interact with full-length tau in a complex with Hsc70/Hsp70 and poly-ubiquitinated tau [17].

p(HGNC:STUB1) increases complex(p(HGNC:HSPA8), p(HGNC:MAPT, pmod(Ub)), p(HGNC:STUB1)) View Subject | View Object

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Evidence 824367d838
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After cyclohexamide treatment, we could still detect a significant decrease in tau levels in cells that were co-transfected with CHIP indicating that the reduction in tau levels due to CHIP is due to degradation and not to transcriptional down-regulation (Supplementary Fig. 3).

p(HGNC:STUB1) increases deg(p(HBP:"4R tau", var("p.Lys280del"))) View Subject | View Object

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composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) decreases p(HBP:"4R tau", var("p.Lys280del")) View Subject | View Object

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Evidence 9dc93fcda6
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Tau overexpression increased active caspase 3 levels, and co-expression of CHIP reduced cleaved caspase 3 levels compared to tau expression alone (Fig. 3).

p(HBP:"Tau C3") positiveCorrelation act(p(HGNC:CASP3)) View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)") positiveCorrelation act(p(HGNC:CASP3)) View Subject | View Object

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composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) decreases p(HGNC:CASP3, frag("?")) View Subject | View Object

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composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) decreases p(HGNC:CASP3, frag("?")) View Subject | View Object

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act(p(HGNC:CASP3)) positiveCorrelation p(HBP:"Tau isoform F (441 aa)") View Subject | View Object

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act(p(HGNC:CASP3)) positiveCorrelation p(HBP:"Tau C3") View Subject | View Object

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Evidence 9e0eacbf0e
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Interestingly, a significant decrease in tau levels was seen with the co-transfection of CHIPΔU (U-box deleted) when transfected with either K18ΔK280 or 4R-Tau.

complex(p(HGNC:STUB1), p(INTERPRO:"U box domain")) increases p(HBP:"Tau isoform F (441 aa)") View Subject | View Object

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complex(p(HGNC:STUB1), p(INTERPRO:"U box domain")) increases p(HBP:"4R tau", var("p.Lys280del")) View Subject | View Object

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Evidence 693fe9f6f9
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Densitometry analysis of total tau levels of H4- cell lysates on SDS-PAGE showed a 2.0 to 2.5 fold lower levels of tau (4R-tau, tauC3, and K18ΔK280) with co-expression with CHIP, respectively (Fig. 1).

composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) decreases p(HBP:"4R tau", var("p.Lys280del")) View Subject | View Object

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composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) decreases p(HBP:"Tau C3") View Subject | View Object

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composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) decreases p(HBP:"Tau isoform F (441 aa)") View Subject | View Object

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Evidence 4f32369f11
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Probing for phospho-tau with the 12E8 antibody in cell lysates from K18ΔK280 transfected cells reveals that tau phosphorylation is also decreased by CHIP overexpression (Fig. 1).

composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) negativeCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) negativeCorrelation composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) View Subject | View Object

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Evidence 49124d2f62
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Co-transfection of CHIP with 4R-tau leads to a significant increase in Hsp70 levels, however this is not the case with wither tauC3 or K18DK280 constructs (Supplementary Fig. 2) suggesting that increased HSP70 protein levels are not necessary for the observed reduction in tau levels.

composite(p(HBP:"4R tau", var("p.Lys280del")), p(HGNC:STUB1)) causesNoChange a(MESH:"HSP70 Heat-Shock Proteins") View Subject | View Object

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composite(p(HBP:"Tau C3"), p(HGNC:STUB1)) causesNoChange a(MESH:"HSP70 Heat-Shock Proteins") View Subject | View Object

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composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) increases a(MESH:"HSP70 Heat-Shock Proteins") View Subject | View Object

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Evidence ed151dd0b1
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Indeed, the co-expression of CHIP caused a significant decrease tauC3 in vitro (Fig. 4).

composite(p(HBP:"Tau isoform F (441 aa)"), p(HGNC:STUB1)) decreases p(HBP:"Tau C3") View Subject | View Object

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Evidence f0615f14c9
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In CHIP knockout mice, Caspase 3 activation is increased and caspase-cleaved tau levels are increased [17].

p(MGI:Stub1) decreases act(p(MGI:Casp3)) View Subject | View Object

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p(MGI:Stub1) decreases p(HBP:"Tau C3") View Subject | View Object

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Evidence edf317192f
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CHIP has two important domains for his chaperone activity: the amino terminus tetratricopeptide repeat (TPR) domain that links CHIP to Hsp70 and Hsp90 [24] and the carboxyl terminus containing the U-box that is important for the E3 ubiquitin ligase function of CHIP.

p(PFAM:"CHIP_TPR_N") increases complex(a(MESH:"HSP70 Heat-Shock Proteins"), p(FPLX:HSP90), p(HGNC:STUB1)) View Subject | View Object

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