Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins

Tripathi, Vishwadeepak; Darnauer, Stefanie; Hartwig, Nadine R.; Obermann, Wolfgang M. J.

doi:10.1074/jbc.m114.590141

Cited by 26 publications

(30 citation statements)

References 34 publications

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“…The results confirm that Leishmania Aha1 behaves similarly to other known Aha1 orthologues (Chua et al 2012;Panaretou et al 2002;Singh et al 2014). Whether Leishmania Aha1 has interaction partners other than Hsp90 or chaperone activity by itself as described for human Aha1 (Tripathi et al 2014) remains to be investigated.…”

Section: Aha1supporting

confidence: 70%

Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation

Bartsch

Hombach-Barrigah

Clos

2017

Cell Stress and Chaperones

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Hsp90 and its co-chaperones are essential for the medically important parasite Leishmania donovani, facilitating life cycle control and intracellular survival. Activity of Hsp90 is regulated by co-chaperones of the Aha1 and P23 families. In this paper, we studied the expression of L. donovani Aha1 in two life cycle stages, its interaction with Hsp90 and the phenotype of Aha1 null mutants during the insect stage and inside infected macrophages. This study provides a detailed in vitro analysis of the function of Aha1 in Leishmania parasites and the first instance of a reverse genetic analysis of Aha1 in a protozoan parasite. While Aha1 is non-essential under standard growth conditions and at elevated temperature, Aha1 protects against ethanol stress. However, both overexpression and lack of Aha1 affected parasite growth in the presence of the Hsp90 inhibitors radicicol (RAD) and geldanamycin (GA). Under RAD pressure, P23 and Aha1 act in an antagonistic way. By contrast, expression levels of both co-chaperones have similar effects under GA treatment, indicating different inhibition mechanisms by the two compounds. Aha1 is also secreted in virulenceenhancing exosomes. This may explain why the loss of Aha1 reduces the infectivity of L. donovani in ex vivo mouse macrophages, indicating a role during the intracellular mammalian stage.

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Section: Aha1supporting

confidence: 70%

Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation

Bartsch

Hombach-Barrigah

Clos

2017

Cell Stress and Chaperones

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“…HSP90AA1 is already known as a universal biomarker indicating heat stress, in mammals and fish (Buckley et al, 2006 ; Quinn et al, 2011a , b ; Anttila et al, 2014 ; Jeffries et al, 2014 ; Tomalty et al, 2015 ; Verleih et al, 2015 ). The ATPase activity of HSP90 is stimulated by AHSA1, which chaperones its own client proteins (Tripathi et al, 2014 ). In line with this, AHSA1 has been identified as heat-shock responsive in Chinook salmon (Tomalty et al, 2015 ) and channel catfish (Liu et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Gradual and Acute Temperature Rise Induces Crossing Endocrine, Metabolic, and Immunological Pathways in Maraena Whitefish (Coregonus maraena)

et al. 2018

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The complex and still poorly understood nature of thermoregulation in various fish species complicates the determination of the physiological status on the basis of diagnostic marker genes and indicative molecular pathways. The present study aimed to compare the physiological impacts of both gradual and acute temperature rise from 18 to 24°C on maraena whitefish in aquaculture. Microarray-based transcriptome profiles in the liver, spleen and kidney of heat-stressed maraena whitefish revealed the modulation of a significantly higher number of genes in those groups exposed to gradually rising temperatures compared with the acutely stressed groups, which might reflect early adaptation mechanisms. Moreover, we suggest a common set of 11 differentially expressed genes that indicate thermal stress induced by gradual or acute temperature rise in the three selected tissues. Besides the two pathways regulated in both data sets unfolded protein response and aldosterone signaling in epithelial cells, we identified unique tissue- and stress type-specific pathways reflecting the crossroads between signal transduction, metabolic and immunologic pathways to cope with thermal stress. In addition, comparing lists of differentially regulated genes with meta-analyzed published data sets revealed that “acute temperature rise”-responding genes that encode members of the HSP70, HSP90, and HSP40 families; their functional homologs; co-chaperones and stress-signal transducers are well-conserved across different species, tissues and/or cell types and experimental approaches.

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“…While the ability of Aha1 to bind to its clients has been shown to require the first 22 amino acids located at the NTD of Aha1 17,39 , which is unaffected by SEW, the ATPase stimulating activity in vitro required the full-length protein. These data suggest that while SEW04784 is unlikely to disrupt the ability of Aha1 to bind to its client proteins, it potentially could also impact the chaperoning activity of Aha1, thereby promoting the clearance of bound clients, such as p-tau and the AR, through ubiquitination, as shown tau in response to co-incubation with IU1-47 117 or for Aha1-bound, heat denatured FLuc in the absence of chaperone-mediated refolding 25 . Therefore, the ability of SEW to mediate a reduction in tau aggregation and/or block the activity of AR missense variants in prostate cancer could be the concerted action of both inhibiting the ASH activity and the chaperone activity of Aha1.…”

Section: Role Of Aha1 In Tauopathymentioning

confidence: 94%

“…While the cellular function of Aha1 is often exclusively considered in the context of its cochaperoning activity as an ATPase stimulating co-factor for Hsp90, the majority of Aha1 exists in an Hsp90-free state in human cells 25 . While this mutual exclusion observation could be explained by the co-chaperone activity of Aha1, which shifts the binding equilibrium of the Hsp90/Aha1 interaction to the non-bound state, Aha1 was able to prevent the aggregation of both FLuc and Rhodanese in vitro and in vivo in the absence of Hsp90, suggesting that it possesses direct chaperoning activity.…”

Section: Role Of Aha1 In Tauopathymentioning

confidence: 99%

Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone

Singh

Tait²,

Guy

et al. 2018

Preprint

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The core cytosolic Hsp90 chaperone/co-chaperone complex plays a critical role in proteostasis management of human health and disease. To identify novel compounds that alter the ability of the Hsp90 co-chaperone Aha1 to modulate the ATPase activity found in multiple folding diseases ranging from steroid hormone receptor (SHR) sensitive prostate cancer to tauopathies associated with neurodegenerative diseases, we employed a high throughput screening (HTS) assay to monitor selectively Aha1stimulated Hsp90 (ASH) ATPase activity. The ASH assay identified SEW04784 (SEW), a small molecule that disrupts ASH activity without inhibiting the basal Hsp90 ATPase activity. NMR analysis reveals that SEW binds to the C-terminal domain of Aha1 to disrupt its asymmetric binding to Hsp90 leading to abrogation of its chaperoning activity of Hsp90. SEW exhibits therapeutic potential by blocking the transcriptional activity of prostate cancer (PCa) associated variants of the androgen receptor (AR) in a cell-based model of PCa. Additionally, SEW exhibits the ability to clear toxic, phosphorylated tau aggregated species associated with tauopathies. By not directly impacting the basal ATPase function of the abundant and ubiquitous Hsp90, SEW could provide a therapeutic approach for mitigation of client-specific proteostatic disease.of TPR containing co-chaperones via its MEEVD motif 5,14 . The Hsp90 dimer undergoes a series of structural rearrangements during its ATP-binding and hydrolysis cycle. In the nucleotide-free (apo) form, the C-terminally dimerized Hsp90 adopts an open conformation, which closes upon ATP binding and hydrolysis, a process that promotes protein folding and is assisted by the action of its multiple co-chaperones 5,14 , including the accelerator of Hsp90 ATPase (Aha1) 17-32 .Aha1 is a two domain, Hsp90 co-chaperone conserved from yeast to man 21,23,[33][34][35] . It competes with other Hsp90 co-chaperones for binding to Hsp90 and contributes to the functional activation of client proteins, including kinases, steroid hormone receptors and transcription factors 1,4,5,33,36,37 , by stimulating the ATPase activity of Hsp90 [38][39][40] . We have previously shown that Aha1 binding to Hsp90 is asymmetric. It bridges the middle domain of one of the Hsp90 protomers in the Hsp90 dimer with the N-terminal domain of the other Hsp90 molecule to promote the N-terminal dimerization of Hsp90 and thereby stimulate its ATPase activity [38][39][40] . The silencing of Aha1 decreases client protein activation and increases cellular sensitivity to Hsp90 inhibitors 38,41,42 . In cystic fibrosis (CF), a reduction of the Aha1 expression levels in vivo corrects the trafficking and functional defect associated with the deletion of Phe508 (F508del) variant of the cystic fibrosis transmembrane conductance regulator (CFTR), the most abundant CF-associated mutation 32 . These data suggest an important role for reduced ATPase activity in the stabilization of mutant CFTR, a hypothesis that we posited can be extended to other Hsp90-associated disea...

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Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins

Cited by 26 publications

References 34 publications

Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation

Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation

Gradual and Acute Temperature Rise Induces Crossing Endocrine, Metabolic, and Immunological Pathways in Maraena Whitefish (Coregonus maraena)

Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone

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