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Appears in Networks 7

In-Edges 20

a(HBP:"Tau aggregates") association p(HGNC:HDAC6) View Subject | View Object

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014). PubMed:29311797

p(HBP:"microtubule-binding region") association p(HGNC:HDAC6) View Subject | View Object

Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the PubMed:26751493

p(HGNC:MAPT) decreases act(p(HGNC:HDAC6)) 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

a(CHEBI:vorinostat) directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

Appears in Networks:

a(GO:microtubule) negativeCorrelation act(p(HGNC:HDAC6)) View Subject | View Object

Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. PubMed:23487739

Appears in Networks:

a(HBP:"ACY-1215") directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

a(HBP:"Tau epitope, 12E8") positiveCorrelation act(p(HGNC:HDAC6)) View Subject | View Object

We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events PubMed:25031639

Appears in Networks:

a(HBP:"Tubastatin A") directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

a(HBP:"microtubule-binding region") association p(HGNC:HDAC6) View Subject | View Object

Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the PubMed:26751493

Appears in Networks:

a(HBP:MPT0G211) directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Appears in Networks:

a(HBP:Trithiocarbonates) directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug. PubMed:18558669

Appears in Networks:

a(HBP:Tubacin) directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. PubMed:23487739

Appears in Networks:

a(HBP:crebinostat) directlyDecreases act(p(HGNC:HDAC6)) View Subject | View Object

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

Appears in Networks:

p(HGNC:MAPT) positiveCorrelation p(HGNC:HDAC6) View Subject | View Object

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Appears in Networks:

p(FPLX:Tubulin, pmod(Ac)) negativeCorrelation act(p(HGNC:HDAC6)) View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

p(HGNC:CTNNB1, pmod(Ac, Lys, 49)) negativeCorrelation act(p(HGNC:HDAC6)) View Subject | View Object

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 324)) positiveCorrelation p(HGNC:HDAC6) View Subject | View Object

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Appears in Networks:

act(p(INTERPRO:"Heat shock protein Hsp90 family")) positiveCorrelation act(p(HGNC:HDAC6)) View Subject | View Object

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Appears in Networks:

bp(GO:"protein K63-linked ubiquitination") increases act(p(HGNC:HDAC6)) View Subject | View Object

Specifically, it is suggested that K63-linked polyubiquitin chains recruit p62 and HDAC6 providing a signal for autophagic degradation [92,93]. PubMed:18930136

a(PUBCHEM:53340666) association p(HGNC:HDAC6) View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Out-Edges 23

p(HGNC:HDAC6) decreases a(HBP:HBP00093) View Subject | View Object

Finally, inhibition of histone deacetylase 6 (HDAC6), which was previously shown to be involved in the response to cytotoxic ubiquitinated aggregates, increased the oligomeric content in vitro, while overexpression of HDAC6 produced the opposite effect [36]. PubMed:28803412

p(HGNC:HDAC6) increases act(p(HGNC:AIP)) View Subject | View Object

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014). PubMed:29311797

p(HGNC:HDAC6) association a(HBP:"Tau aggregates") View Subject | View Object

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014). PubMed:29311797

p(HGNC:HDAC6) association p(HBP:"microtubule-binding region") View Subject | View Object

Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the PubMed:26751493

p(HGNC:HDAC6) association a(HBP:"microtubule-binding region") View Subject | View Object

Apart from binding to MT, the repeat domains of tau also bind to tubulin deacetylase, histone deacetylase 6 (HDAC6) [68] and apolipoprotein E (apoE) more with the PubMed:26751493

Appears in Networks:

act(p(HGNC:HDAC6)) positiveCorrelation a(HBP:"Tau epitope, 12E8") View Subject | View Object

We demonstrate that elevated HDAC6 activity increases phosphorylation of tau at the 12E8 epitope (pS262/356), a phospho-epitope present within the KXGS motifs of tau’s microtubule-binding domain. The phosphorylation of KXGS motifs within tau by the kinase Par-1/MARK2 is required for tau proteotoxicity in Drosophila [29], observed at very early stages of NFT formation in AD brain [30], and appears to prime tau for subsequent phosphorylation events PubMed:25031639

Appears in Networks:

act(p(HGNC:HDAC6)) negativeCorrelation p(FPLX:Tubulin, pmod(Ac)) View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

act(p(HGNC:HDAC6)) negativeCorrelation p(HGNC:CTNNB1, pmod(Ac, Lys, 49)) View Subject | View Object

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

Appears in Networks:

act(p(HGNC:HDAC6)) negativeCorrelation a(GO:microtubule) View Subject | View Object

Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. PubMed:23487739

Appears in Networks:

act(p(HGNC:HDAC6)) decreases p(INTERPRO:"Tubulin/FtsZ, GTPase domain", pmod(Ac)) View Subject | View Object

Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. PubMed:23487739

Appears in Networks:

p(HGNC:HDAC6) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Appears in Networks:

p(HGNC:HDAC6) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 324)) View Subject | View Object

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Appears in Networks:

act(p(HGNC:HDAC6)) positiveCorrelation act(p(INTERPRO:"Heat shock protein Hsp90 family")) View Subject | View Object

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Appears in Networks:

p(HGNC:HDAC6) regulates bp(GO:autophagy) 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:HDAC6) increases bp(GO:autophagy) View Subject | View Object

Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136

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:HDAC6) regulates a(GO:aggresome) 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:HDAC6) increases tloc(p(MESH:Proteins, pmod(Ub)), fromLoc(GO:cytoplasm), toLoc(GO:lysosome)) View Subject | View Object

HDAC6 activity appears to be important for trafficking ubiquitinated proteins and lysosomes in vitro and this has led to the suggestion that HDAC6 coordinates delivery of substrates to autophagic machinery [64,70,78]. PubMed:18930136

p(HGNC:HDAC6) increases bp(GO:"Hsp90 deacetylation") View Subject | View Object

HDAC6 activity was also reported to regulate chaperone expression in response to heat shock by deacetylating Hsp90 leading to release and activation of the transcription factor HSF-1 [79]. PubMed:18930136

p(HGNC:HDAC6) regulates complex(GO:"chaperone complex") View Subject | View Object

HDAC6 activity was also reported to regulate chaperone expression in response to heat shock by deacetylating Hsp90 leading to release and activation of the transcription factor HSF-1 [79]. PubMed:18930136

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

Recent models propose that p62 and HDAC6 function analogously to facilitate autophagic degradation of proteins that display specific polyubiquitin topology. PubMed:18930136

p(HGNC:HDAC6) association a(PUBCHEM:53340666) View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

p(HGNC:HDAC6) decreases p(HGNC:MAPT, pmod(Ac, Lys)) View Subject | View Object

Tau can be acetylated by the P300 acetyltransferase or by CREB-binding protein at several Lys residues in the flanking region or the repeat domain, and deacetylated at these sites by sirtuin 1 (SIRT1) and histone deacetylase 6 (HDAC6), respectively PubMed:26631930

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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.