A DNAJB Chaperone Subfamily with HDAC-Dependent Activities Suppresses Toxic Protein Aggregation

Hageman, Jurre; Rujano, Maria A.; Waarde, Maria A.W.H. van; Kakkar, Vaishali; Dirks, Ron P.; Govorukhina, Natalia; Oosterveld-Hut, Henderika M.J.; Lubsen, Nicolette H.; Kampinga, Harm H.

doi:10.1016/j.molcel.2010.01.001

Cited by 333 publications

(582 citation statements)

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“…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. The Dm ortholog of the human DNAJB6, MRJ, previously identified in a screen for suppressors of polyglutamine (polyQ) toxicity (Fayazi et al ., 2006; Hageman et al ., 2010) was used as a positive control and indeed completely inhibited aggregate formation in S2 cells as demonstrated using filter trap binding (Fig. 4A).…”

Section: Resultsmentioning

confidence: 74%

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: 74%

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

et al. 2015

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“…All these studies have identified genes belonging to distinct classes including genes involved in RNA metabolism (RNA pol II subunits, splicing factors), protein synthesis (ribosomes, initiation and elongation factors), protein folding (chaperones) and protein degradation (proteasome subunits and autophagy factors). The role of molecular chaperones, particularly Hsp70 and Hsp40, in suppressing Htt aggregation and its associated toxicity has been extensively elucidated using different experimental approaches (Hageman et al, 2010;Muchowski et al, 2000;Sakahira et al, 2002;Warrick et al, 1999;Wyttenbach et al, 2000). Besides molecular chaperones, cells have evolved distinct mechanisms to protect themselves from accumulation of toxic protein species.…”

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

“…However, among these different Hsp40 members, only DnaJB1 has been studied in detail. In HEK 293T cells, DnaJB1 is moderately expressed and is highly inducible upon heat stress (Hageman et al, 2010;Hageman et al, 2011). It has been shown that DnaJB1 suppresses the aggregation of polyQ proteins (Rujano et al, 2007;Zijlstra et al, 2010) and also prevents luciferase aggregation during heat stress (Hageman et al, 2010).…”

Section: Vi8 Role Of Dnajb1 In the Degradation Of Proteinsmentioning

confidence: 99%

“…In HEK 293T cells, DnaJB1 is moderately expressed and is highly inducible upon heat stress (Hageman et al, 2010;Hageman et al, 2011). It has been shown that DnaJB1 suppresses the aggregation of polyQ proteins (Rujano et al, 2007;Zijlstra et al, 2010) and also prevents luciferase aggregation during heat stress (Hageman et al, 2010). Moreover, it has been demonstrated that overexpression of Hsp70 and DnaJB1 facilitates the degradation of polyQ expanded forms of the androgen receptor (Bailey et al, 2002).…”

Section: Vi8 Role Of Dnajb1 In the Degradation Of Proteinsmentioning

confidence: 99%

“…Moreover, it has been demonstrated that overexpression of Hsp70 and DnaJB1 facilitates the degradation of polyQ expanded forms of the androgen receptor (Bailey et al, 2002). Recently, it has also been shown that less characterized members of the DnaJB family, DnaJB6 and DnaJB8, bind non-foldable clients such as polyQ proteins and keep them in a state competent for (proteasomal) degradation (Hageman et al, 2010;Kampinga and Craig, 2010). This suggests that DnaJ proteins, besides participating in folding also play an important role in preventing the accumulation of misfolded proteins by targeting them for proteasome mediated degradation.…”

Section: Vi8 Role Of Dnajb1 In the Degradation Of Proteinsmentioning

confidence: 99%

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Firefly luciferase mutants as sensors of proteome stress

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HSP40 / DNAJ Chaperones

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Encyclopedia of Life Sciences

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Members of the HSP40/DNAJ family comprise one of the largest groups of molecular chaperones, and are present in all living organisms from bacteria to humans. The hallmark of DNAJs is the presence of a J‐domain, which is crucial for interaction with HSP70. DNAJs can be seen as the workforce that steers HSP70 machines, regulating client input and specificity. The different DNAJs are involved in processes such as (re)folding, intracellular transport across membranes, protein modifications, remodelling of protein complexes and protein degradation. In particular, different DNAJs are able to suppress aggregate formation of several amyloidogenic proteins linked to human diseases. On the other hand, mutations in many DNAJs give rise to a wide range of pathologies, attesting to their fundamental role in cellular homeostasis and general protein quality control. Key Concepts Chaperome is the interconnected network of chaperones and cochaperones that works cooperatively to maintain protein homeostasis (Brehme and Voisine, 2016). Molecular chaperone is a protein that assists folding, refolding, disaggregation and/or assembly of macromolecular complexes, but is not a permanent component of the final, native, functional structure. Chaperones can act as substrate ‘foldases’ in an ATP‐dependent manner or as ‘holdases’ in an ATP‐independent manner. Folding is the formation of an energetically stable three‐dimensional conformation specific to a given protein sequence, also known as the native, functional conformation. On the other hand, misfolding happens when the protein does not reach its native conformation on a biologically relevant timescale. Amyloidogenic proteins are proteins with a high tendency of folding into energetically favourable aggregates, which catalyse the formation of protein fibrils and plaques, and are associated to cellular toxicity and degeneration. Protein disaggregation is the disentangling of protein aggregates through their resolubilization by chaperones, followed by their refolding or degradation.

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A DNAJB Chaperone Subfamily with HDAC-Dependent Activities Suppresses Toxic Protein Aggregation

Cited by 333 publications

References 45 publications

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

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

Firefly luciferase mutants as sensors of proteome stress

HSP40 / DNAJ Chaperones

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