HspB8 and Bag3: A new chaperone complex targeting misfolded proteins to macroautophagy

Carra, Serena; Seguin, Samuel J.; Landry, Jacques

doi:10.4161/auto.5407

Cited by 211 publications

(217 citation statements)

References 23 publications

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“…Several protein folding diseases are characterized by the formation of toxic aggregates such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Some small HSPs have been reported to suppress the aggregation of such disease‐related proteins (Wilhelmus et al ., 2006; Carra et al ., 2008), and we have found that this is not always related to their capacity to refold heat‐denatured luciferase (Vos et al ., 2010). Therefore, we tested which of the Drosophila small HSPs could suppress aggregation of an EGFP‐tagged huntingtin exon‐1 containing 119 glutamines (EGFP‐HDQ119) in S2 cells.…”

Section: Resultsmentioning

confidence: 86%

“…By their ability to bind non‐native polypeptides, they maintain their substrates in a state competent for subsequent folding or, when folding is not successful, for degradation by the ubiquitin–proteasome system (Urushitani et al ., 2004) or through autophagy (Carra et al ., 2008). Hereby chaperones can prevent toxic protein aggregation, and as such, they have been implicated as protectors against age‐related protein folding diseases (Rujano & Kampinga, 2008) and as supporters of healthy aging (Hsu et al ., 2003; Morrow & Tanguay, 2003; Walker & Lithgow, 2003; Morley & Morimoto, 2004; Morimoto, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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SummaryDuring aging, oxidized, misfolded, and aggregated proteins accumulate in cells, while the capacity to deal with protein damage declines severely. To cope with the toxicity of damaged proteins, cells rely on protein quality control networks, in particular proteins belonging to the family of heat‐shock proteins (HSPs). As safeguards of the cellular proteome, HSPs assist in protein folding and prevent accumulation of damaged, misfolded proteins. Here, we compared the capacity of all Drosophila melanogaster small HSP family members for their ability to assist in refolding stress‐denatured substrates and/or to prevent aggregation of disease‐associated misfolded proteins. We identified CG14207 as a novel and potent small HSP member that exclusively assisted in HSP70‐dependent refolding of stress‐denatured proteins. Furthermore, we report that HSP67BC, which has no role in protein refolding, was the most effective small HSP preventing toxic protein aggregation in an HSP70‐independent manner. Importantly, overexpression of both CG14207 and HSP67BC in Drosophila leads to a mild increase in lifespan, demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo.

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Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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“…HSPB8 acts in a complex with BAG3 (11), a member of the BAG family of proteins (29 -31), and the complex facilitates the clearance of misfolded aggregate-prone proteins (11,32,33). In the current study, we first identified HSP67Bc as a D. melanogaster functional ortholog of human HSPB8, and we show that, like HSPB8, Dm-HSP67Bc interacts with Starvin, the sole BAG D. melanogaster protein (34), and that Dm-HSP67Bc stimulates autophagy.…”

mentioning

confidence: 99%

Identification of the Drosophila Ortholog of HSPB8

Carra

Boncoraglio

Kanon

et al. 2010

Journal of Biological Chemistry

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Protein aggregation is a hallmark of many neuronal disorders, including the polyglutamine disorder spinocerebellar ataxia 3 and peripheral neuropathies associated with the K141E and K141N mutations in the small heat shock protein HSPB8. In cells, HSPB8 cooperates with BAG3 to stimulate autophagy in an eIF2␣-dependent manner and facilitates the clearance of aggregate-prone proteins (Carra, S., Seguin, S. J., Lambert, H., and Landry, J. (2008) In vitro, both Dm-HSP67Bc and human HSPB8 protected against mutated ataxin-3-mediated toxicity and decreased the aggregation of a mutated form of HSPB1 (P182L-HSPB1) associated with peripheral neuropathy. Upregulation of both Dm-HSP67Bc and human HSPB8 protected and down-regulation of endogenous Dm-HSP67Bc significantly worsened SCA3-mediated eye degeneration in flies. The K141E and K141N mutated forms of human HSPB8 that are associated with peripheral neuropathy were significantly less efficient than wild-type HSPB8 in decreasing the aggregation of both mutated ataxin 3 and P182L-HSPB1. Our current data further support the link between the HSPB8-BAG3 complex, autophagy, and folding diseases and demonstrate that impairment or loss of function of HSPB8 might accelerate the progression and/or severity of folding diseases.Aggregation of misfolded mutated proteins and neuronal loss are hallmarks of many neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and polyglutamine disorders (e.g. Huntington disease and spinocerebellar ataxia 3), which are often referred to as protein conformational disorders (1, 2). Moreover, aggregation of mutated proteins is also commonly observed in several types of neuromuscular and muscular disorders (e.g. Charcot-Marie-Tooth type 1A, desmin-related myopathy, and muscular dystrophy), thus further underscoring a causal role for protein misfolding in neuronal and muscular cell degeneration (3-6). Hence, suppression of protein aggregation and acceleration of protein removal are considered to be common therapeutic approaches to treat the protein conformational disorders (7,8). Both suppression of protein aggregation and degradation of misfolded proteins can be achieved through stimulation of the protein quality control system, which includes molecular chaperones of the heat shock protein (HSP) 3 families and degradation systems (proteasome, chaperone-mediated autophagy, and macroautophagy) (8). It has been shown that up-regulation of molecular chaperones and stimulation of autophagy can protect from the toxic effects of aggregating proteins both in cellular and animal (e.g. Drosophila melanogaster) models of protein conformation disorders (9 -12). Conversely, impairment of molecular chaperone function may have detrimental effects for cellular viability, and failure of the HSP system with age is a likely relevant factor to the age of onset of protein misfolding diseases and for the aging process itself (13). Intriguingly, mutations in several members of the human small HSP family, which includes 10 members (sHSP/HSPB; HSPB1-HSPB...

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“…The proteasome would selectively handle the soluble form and insoluble small oligomers (34,66), while autophagy would be involved in aggregate destruction (42,59,64,67). In support of this later possibility, BAG3 has recently been shown to stimulate autophagy in a complex with the sHSP HspB8 (8).…”

Section: The Pleiotropic Roles Of Cardiac Hdac3mentioning

confidence: 82%

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

Mustafi

Grose

Zhang

et al. 2014

Antioxidants & Redox Signaling

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Aims: The human mutation R120G in the aB-crystallin (CRYAB) causes a multisystemic disease that is characterized by hypertrophic cardiomyopathy and cytoplasmic protein aggregates. In transgenic mice, human R120GCRYAB (hR120GTg) expression in heart sequentially modifies the REDOX status, in part by the activation of the nuclear factor, erythroid derived 2, like 2 (Nrf2). Thioredoxin system (TS) components are NRF2 target genes, so it could be hypothesized that TS was affected in hR120GTg mice. Results: Transgenic hearts overexpressed thioredoxin 1 (Trx1), which was identified by isotope coded affinity tag-mass spectrometry, among hundreds of peptides displaying an increased reduced/oxidized ratio. Coupled to this higher level of reduced cysteines, the activity of thioredoxin reductase 1 (TrxR1) was augmented by 2.5-fold. Combining mutiple experimental approaches, the enzymatic regulation of TrxR1 by a histone deacetylase 3 (HDAC3)-dependent level of acetylation was confirmed. In vitro and in vivo functional tests established that TrxR1 activity is required to mitigate aggregate development, and this could be mediated by Bcl-2-associated athanogene 3 (BAG3) as a potential TS substrate. Innovation and Conclusions: This study uncovers the compartmentalized changes and the involvement of TS in the cardiac stress response elicited by misfolded proteins such as R120GCRYAB. Our work suggests that R120GCRYAB triggers a defensive pathway acting through the newly identified interacting partners HDAC3, TrxR1, and BAG3 to counter aggregate growth. Therefore, those interactors may function as modifier genes contributing to the variable onset and expressivity of such human diseases. Furthermore, our work underscores the potential organismal effects of pharmacological interventions targeting TS and HDAC.

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HspB8 and Bag3: A new chaperone complex targeting misfolded proteins to macroautophagy

Cited by 211 publications

References 23 publications

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Identification of the Drosophila Ortholog of HSPB8

Aggregate-Prone R120GCRYAB Triggers Multifaceted Modifications of the Thioredoxin System

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