BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions

Alberti, Simon; Esser, Claudia; Höhfeld, Jörg

doi:10.1379/1466-1268(2003)008<0225:bnefoh>2.0.co;2

Cited by 136 publications

(91 citation statements)

References 59 publications

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“…Ubiquitination of misfolded HSPA8 clients involves the E3 ligase CHIP, 6 and is modulated by co-chaperones of the Bcl-2-associated athanogene (BAG) family, although the precise role of HSPA8 and these associated molecules in DRiPs processing and subsequent MHCIrestricted presentation has not been extensively addressed. 36,37 BAG proteins have been reported to facilitate the degradation of Hsp70/HSPA8 substrates by the proteasome or through autophagy, 7,29,[38][39][40][41] and are therefore likely to also participate in the quality control mechanisms regulating GFP-SL8 DRiPs folding and degradation. We silenced different mRNAs coding for HSPA8 42 and associated BAG co-chaperones.…”

Section: Do Not Distributementioning

confidence: 99%

Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

et al. 2012

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Till Wenger and Seigo Terawaki contributed equally to this work; 4 Evelina Gatti and Philippe Pierre contributed equally to this work.Keywords: NBR1, SQSTM1, ATG5, antigen presentation, DRiPs A significant portion of newly synthesized protein fails to fold properly and is quickly degraded. These defective ribosomal products (DRiPs) are substrates for the ubiquitin-proteasome system (UPS) and give rise to a large fraction of peptides presented by major histocompatibility complex class I molecules (MHCI). Here, we showed that DRiPs are also autophagy substrates, which accumulate upon autophagy inhibition in aggresome-like-induced structures (ALIS). Aggregation is critically depending on p62/SQSTM1, but occurs in the absence of activation of the NRF2 signaling axis and transcriptional regulation of p62/SQSTM1. We demonstrated that autophagy-targeted DRiPs can become UPS substrates and give rise to MHCI presented peptides upon autophagy inhibition. We further demonstrated that autophagy targeting of DRiPs is controlled by NBR1, but not p62/SQSTM1, CHIP or BAG-1. Active autophagy therefore directly modulates MHCI presentation by constantly degrading endogenous defective neosynthesized antigens, which are submitted to at least two distinct quality control mechanisms.

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Section: Do Not Distributementioning

confidence: 99%

Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

et al. 2012

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“…Another example is: cochaperone nucleotide-exchange factor BCell lymphoma athanogene 2-associated 1 (BAG-1) facilitates ATP-ADP cycle and assists with Hsp70 protein folding. Chaperone-cochaperone complex helps newly translated protein folding and fold to make a return to the denatured protein, or protein molecules to steer proteases to degrade if the protein cannot be saved [22][23][24]. Distinguishing functional domains of molecular chaperones can recognize a polypeptide chain that need help, interconnected and form a complex folding chaperone and perform again, or associated with another chaperone complex, by a machine degradating protein, such as ubiquitin-proteasome system to degrade.…”

Section: Discussionmentioning

confidence: 99%

“…Distinguishing functional domains of molecular chaperones can recognize a polypeptide chain that need help, interconnected and form a complex folding chaperone and perform again, or associated with another chaperone complex, by a machine degradating protein, such as ubiquitin-proteasome system to degrade. Some chaperones bind ATP and master ATPase activity [24][25][26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 40 (Hsp40) and Hsp70 Protein Expression in Oral Squamous Cell Carcinoma (OSCC)

Prayitno¹,

Asnar²,

Astirin³

et al. 2013

JCT

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Introduction: As a chaperone, heat shock protein acts as central integrators of protein homeostasis in cell. The form of these functions is to help setting up a complex protein molecular fold (folded protein) in many important settings, such as growth, differentiation, and the ability to live. It has become clear that the control system plays an important role if the folding process fails or an error occurs, causing folding abnormalities and targeted functionality to accumulate. The accumulation of faulty protein folding would harm cells and can result in death. Apparently, there is a correlation between protein folding error with various diseases, such as diabetes mellitus and cancer. Method: We examined protein levels in all samples using Dotblott with monoclonal antibody anti-Hsp40 and anti-Hsp70. Levels of the protein content was read using a densitometer. Modification of Dot Blot was as follows: treatment was conducted with 3 × SSC, added with 20 mL blocking solution, add with total protein samples of 10 mg/ml on nitrocellulose paper, prehybridized, incubated at 70˚ for 30 seconds, incubated at 70˚ for 30 seconds with primary antibody anti-Hsp40 or Hsp70 protein and then added with second antibody HRP anti-Hsp40 or Hsp70 protein, treated with 3 × SSC and visualized with TSA HRP, and then administered with streptavidin, biothynil tyramide, and, finally, added with chromogen (DAB) in a confined space. Result: From the analysis of the data using Manova test with Wilk's Lambda, there were significant differences in the levels of Hsp40 between Benign Oral Lesion (mean 688.31 area) and OSCC (mean 1354.59 area) patients (p < 0.070), there was also a highly significant difference in Hsp70 levels between patients who experienced Benign Oral Lesion (mean 529.82 area) and OSCC (mean 1346.32 area) patients (p < 0.006). Conclusion: OSCC patients have increased Hsp70 levels, so it is possible that something is going wrong in protein folding. Errors in protein folding result in a new homeostasis or inhibition of apoptosis and increasing cell proliferation that triggers carcinogenesis. Hsp40 acts as co-chaperones.

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“…Bag-1 is the nucleotide-exchange factor of Hsp70 and is believed to function in the unloading of client proteins from the chaperone. In addition to interaction with chaperone molecules, Bag-1 also associates with the proteasome via its ubiquitin-like (UBL) domain in an ATP-dependent manner and possibly functions as a coupling factor between the chaperones and the proteasomes (Alberti et al 2003). To understand whether Bag-1 plays a role in the CHIP-mediated degradation of mutant SOD1, we examined the interaction between mutant SOD1 and Bag-1 and tested the effect of Bag-1 over-expression on the levels of mutant SOD1 proteins.…”

Section: Mutant Sod1 Interacts With Bag-1mentioning

confidence: 99%

CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

Choi

Lee

2010

Animal Cells and Systems

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Previously we showed that CHIP, a co-chaperone of Hsp70 and E3 ubiquitin ligase, can promote the degradation of mutant SOD1 linked to familial amyotrophic lateral sclerosis (fALS) via a mechanism not involving SOD1 ubiquitylation. Here we present evidence that CHIP functions in the interaction of mutant SOD1 with 26S proteasomes. Bag-1, a coupling factor between molecular chaperones and the proteasomes, formed a complex with SOD1 in an hsp70-dependent manner but had no direct effect on the degradation of mutant SOD1. Instead, Bag-1 stimulated interaction between CHIP and the proteasome-associated protein VCP (p97), which do not associate normally. Over-expressed CHIP interferedwith the association between mutant SOD1 and VCP. Conversely, the binding of CHIP to mutant SOD1 was inhibited by VCP, implying that the chaperone complex and proteolytic machinery are competing for the common substrates. Finally we observed that mutant SOD1 strongly associated with the 19S complex of proteasomes and CHIP over-expression specifically reduced the interaction between S6/S6? ATPase subunits and mutant SOD1. These results suggest that CHIP, together with ubiquitin-binding proteins such as Bag-1 and VCP, promotes the degradation of mutant SOD1 by facilitating its translocation from ATPase subunits of 19S complex to the 20S core particle.

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BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions

Cited by 136 publications

References 59 publications

Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation

Heat Shock Protein 40 (Hsp40) and Hsp70 Protein Expression in Oral Squamous Cell Carcinoma (OSCC)

CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

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