Distinct Isoforms of the Cofactor BAG-1 Differentially Affect Hsc70 Chaperone Function

Lüders, Jens; Demand, Jens; Papp, Oliver; Höhfeld, Jörg

doi:10.1074/jbc.275.20.14817

Cited by 82 publications

(65 citation statements)

References 29 publications

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“…Differential expression of BAG-1 was also recently reported in breast, prostate, colon, and leukemia cell lines (39). Distinct isoforms of BAG-1 were noted to affect Hsc70 chaperone function differently (40). BAG-1 p46 (BAG-1-M) was found to inhibit the Hsp70-mediated refolding of the nonnative polypeptide substrates, whereas BAG-1 p33 (BAG-1-S) stimulated Hsc70 chaperone activity.…”

Section: Bag-1 Isoforms May Have Different Anti-apoptotic Functionsmentioning

confidence: 98%

BAG‐1, An Anti‐Apoptotic Tumour Marker

Tang

2002

IUBMB Life

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SummaryBAG-1 is a multifunctional and anti-apoptotic or anti-cell death protein that interacts with a variety of cellular proteins and affects their functions. On the cell surface, it binds to the cytosolic domain of the growth factor receptors and enhances the protection from cell death triggered by growth factor receptors. In the cytosol, it binds to Bcl-2 and heat shock protein, and modulates their functions. In the nucleus, it binds to a variety of nuclear hormone receptors and inhibits hormone-induced apoptosis. BAG-1 is widely overexpressed in a variety of tumour cell lines and cancer tissues.

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Section: Bag-1 Isoforms May Have Different Anti-apoptotic Functionsmentioning

confidence: 98%

BAG‐1, An Anti‐Apoptotic Tumour Marker

Tang

2002

IUBMB Life

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“…The lysate was centrifuged for 30 min at 30,000 ϫ g, and the resulting supernatant was used as a soluble extract. Rat Hsc70, human BAG-1M, and BAG-1S were purified as described after recombinant expression in baculovirus-infected Sf9 cells (16,21,22). Wheat E1 was also expressed recombinantly in insect cells and purified as described for bacterially expressed E1 (23).…”

Section: Methodsmentioning

confidence: 99%

Ubiquitylation of BAG-1 Suggests a Novel Regulatory Mechanism during the Sorting of Chaperone Substrates to the Proteasome

Alberti

Demand

Esser

et al. 2002

Journal of Biological Chemistry

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179

126

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BAG-1 is a ubiquitin domain protein that links the molecular chaperones Hsc70 and Hsp70 to the proteasome. During proteasomal sorting BAG-1 can cooperate with another co-chaperone, the carboxyl terminus of Hsc70-interacting protein CHIP. CHIP was recently identified as a Hsp70-and Hsp90-associated ubiquitin ligase that labels chaperone-presented proteins with the degradation marker ubiquitin. Here we show that BAG-1 itself is a substrate of the CHIP ubiquitin ligase in vitro and in vivo. CHIP mediates attachment of ubiquitin moieties to BAG-1 in conjunction with ubiquitinconjugating enzymes of the Ubc4/5 family. Ubiquitylation of BAG-1 is strongly stimulated when a ternary Hsp70⅐BAG-1⅐CHIP complex is formed. Complex formation results in the attachment of an atypical polyubiquitin chain to BAG-1, in which the individual ubiquitin moieties are linked through lysine 11. The noncanonical polyubiquitin chain does not induce the degradation of BAG-1, but it stimulates a degradation-independent association of the co-chaperone with the proteasome. Remarkably, this stimulating activity depends on the simultaneous presentation of the integrated ubiquitinlike domain of BAG-1. Our data thus reveal a cooperative recognition of sorting signals at the proteolytic complex. Attachment of polyubiquitin chains to delivery factors may represent a novel mechanism to regulate protein sorting to the proteasome.The control and maintenance of the three-dimensional structure of proteins are prerequisites for cell survival and involve a cooperation of molecular chaperones and energy-dependent proteases (1-4). Molecular chaperones recognize hydrophobic regions exposed on unfolded proteins and stabilize non-native conformations. As a consequence formation of insoluble protein aggregates is prevented, and folding to the native state is promoted. On the other hand, energy-dependent proteases, such as the eukaryotic 26 S proteasome, degrade irreversibly damaged proteins that fail to be folded properly.Selection of proteins for degradation by the proteasome involves ubiquitin conjugation (5-7). A polyubiquitin chain is attached to a protein substrate through the concerted action of a ubiquitin-activating enzyme (E1), 1 a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein isopeptide ligase (E3). In contrast to the presence of only one type of E1 enzyme in the eukaryotic cytosol, E2 and E3 enzymes are recruited from large protein families and mediate a specific recognition of a large repertoire of protein substrates. A polyubiquitin chain generated through the linkage of lysine 48 residues of successive ubiquitin moieties is usually sufficient to target a protein substrate to the proteasome, where finally deubiquitylation, unfolding, and degradation occur.Recent studies shed light onto molecular mechanisms underlying the cooperation of molecular chaperones with the ubiquitin/proteasome system during protein quality control. Two co-chaperones, CHIP and BAG-1, are of central importance in this regard. The CHIP protein was shown to act as a ...

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“…A polypeptide substrate commonly used to study Hsc70 function is firefly luciferase, which has a sensitive and reproducible enzymatic assay. Purified Hsc70 has been shown to assist luciferase refolding in numerous studies (Hohfeld et al, 1995;Minami et al, 1996;Hohfeld and Jentsch, 1997;Terada et al, 1997;Luders et al, 2000;Terada and Mori, 2000). However, in most cases the stress-inducible cochaperone Hsp40 was used, and a direct comparison between all three DJAs with Hsc70 has not yet been reported.…”

Section: Dja Activation Of Hsc70mentioning

confidence: 99%

Multiple 40-kDa Heat-Shock Protein Chaperones Function in Tom70-dependent Mitochondrial Import

Bhangoo

Tzankov

Fan

et al. 2007

MBoC

108

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Mitochondrial preproteins that are imported via the translocase of the mitochondrial outer membrane (Tom)70 receptor are complexed with cytosolic chaperones before targeting to the mitochondrial outer membrane. The adenine nucleotide transporter (ANT) follows this pathway, and its purified mature form is identical to the preprotein. Purified ANT was reconstituted with chaperones in reticulocyte lysate, and bound proteins were identified by mass spectrometry. In addition to 70-kDa heat-shock cognate protein (Hsc70) and 90-kDa heat-shock protein (Hsp90), a specific subset of cochaperones were found, but no mitochondria-specific targeting factors were found. Interestingly, three different Hsp40-related J-domain proteins were identified: DJA1, DJA2, and DJA4. The DJAs bound preproteins to different extents through their C-terminal regions. DJA dominant-negative mutants lacking the N-terminal J-domains impaired mitochondrial import. The mutants blocked the binding of Hsc70 to preprotein, but with varying efficiency. The DJAs also showed significant differences in activation of the Hsc70 ATPase and Hsc70-dependent protein refolding. In HeLa cells, the DJAs increased new protein folding and mitochondrial import, although to different extents. No single DJA was superior to the others in all aspects, but each had a profile of partial specialization. The Hsp90 cochaperones p23 and Aha1 also regulated Hsp90 -preprotein interactions. We suggest that multiple cochaperones with similar yet partially specialized properties cooperate in optimal chaperone-preprotein complexes.

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Distinct Isoforms of the Cofactor BAG-1 Differentially Affect Hsc70 Chaperone Function

Cited by 82 publications

References 29 publications

BAG‐1, An Anti‐Apoptotic Tumour Marker

BAG‐1, An Anti‐Apoptotic Tumour Marker

Ubiquitylation of BAG-1 Suggests a Novel Regulatory Mechanism during the Sorting of Chaperone Substrates to the Proteasome

Multiple 40-kDa Heat-Shock Protein Chaperones Function in Tom70-dependent Mitochondrial Import

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