BAG-2 Acts as an Inhibitor of the Chaperone-associated Ubiquitin Ligase CHIP

Arndt, Verena; Daniel, Christina; Nastainczyk, Wolfgang; Alberti, Simon; Höhfeld, Jörg

doi:10.1091/mbc.e05-07-0660

Cited by 173 publications

(192 citation statements)

References 45 publications

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“…It also inhibits CHIP activity (27). These properties allow it to facilitate maturation of newly synthesized CFTR, diverting the receptor from the proteasome pathway (28). Consistent with this, BAG-2 overexpression increased the sensitivity of cells to ricin (Fig.…”

Section: Hsc70 Cochaperone Activity Determines the Fate Of Dislocatedsupporting

confidence: 60%

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Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

Spooner

Hart

Cook

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states.Hsc70 ͉ Hsp90 ͉ ricin E ndoplasmic-reticulum (ER) associated protein degradation (ERAD) comprises coordinated disposal systems that recognize and remove misfolded and unassembled proteins in the ER, dislocating them across the ER membrane to the cytosol for proteasomal destruction. Degradation is normally facilitated by polyubiquitylation, usually on internal lysyl residues of the target protein. Both membrane-bound and soluble ER proteins can be disposed of by ERAD (1, 2).The plant cytotoxin ricin traffics to the ER lumen of mammalian cells where it is reduced to its RTA and RTB subunits before RTA dislocation (3). RTA does not penetrate the ER membrane directly; instead it exploits pre-existing proteinconducting channels as a nonnative species, mimicking ER proteins dispatched via ERAD (4, 5). Thus, it enters the cytosol in a form susceptible to proteolysis or aggregation. A proportion must evade these fates to gain a catalytic conformation that depurinates target ribosomes, stopping protein synthesis. The paucity of lysine residues in RTA may facilitate uncoupling from ERAD by reducing the potential for polyubiquitylation, thereby hampering proteasomal degradation (6). This, in turn, may provide opportunities for spontaneous or chaperone-assisted folding not normally sanctioned for ERAD substrates.We show an interaction of RTA with the cytosolic heat shock (cognate) protein Hsc70. From the chaperone-bound state, nonnative cytosolic RTA can achieve a catalytic conformation or can be inactivated. Its ultimate fate depends on the activities of ...

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Section: Hsc70 Cochaperone Activity Determines the Fate Of Dislocatedsupporting

confidence: 60%

“…5B). Upon addition of E1, both Hsc70 and CHIP became ubiquitylated, events that occur in vivo that reflect regulation of Hsc70 by CHIP (28). Not all proteins are ubiquitylated in these conditions, for example, BAG-2 inhibits CHIP activity without becoming ubiquitylated (28).…”

Section: Hsc70 Cochaperone Activity Determines the Fate Of Dislocatedmentioning

confidence: 99%

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

Spooner

Hart

Cook

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on previous studies showing that degradation of STUB1 substrates can be modulated by different HSPA8 co-chaperones [43][44][45] it is conceivable that STUB1-dependent degradation of HIF1A by CMA is regulated by HSPA8 co-chaperones. Moreover, it is also possible that STUB1 acts at the lysosome level, mediating the interaction between HIF1A and LAMP2A.…”

Section: Discussionmentioning

confidence: 99%

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Fofo²,

et al. 2013

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The transcription factor hiF1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit hiF1A. recent data showed degradation of hiF1A in the lysosome through chaperone-mediated autophagy (cMA). however the molecular mechanism involved has not been elucidated. This study shows that the KFerQ-like motif, that has been identified in all cMA substrates, is required to mediate the interaction between hiF1A and the chaperone hSpA8. Moreover, mutations in the KFerQ-like motif of hiF1A preclude the interaction with the cMA receptor LAMp2A, thus inhibiting its lysosomal degradation. importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of hiF1A in the lysosome by cMA. indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to hSpA8, both prevent degradation of hiF1A by cMA. Moreover, we show that hiF1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of hiF1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of hiF1A bound to cMA positive lysosomes significantly increase in starved animal livers and the binding of hiF1A to LAMp2A increases in response to serum deprivation. Moreover, excessive degradation of hiF1A by cMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation. leucinylleucinylleucinal/proteasome inhibitor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; RCC, renal cell carcinoma; Serpinb, serpin peptidase inhibitor, clade B/Ovalbumin; SLC2A1, solute carrier family 2 (facilitated glucose transporter)/glucose transporter; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; UPS, ubiquitin-proteasome system; VEGFA, vascular endothelial growth factor A; u-box, modified RING finger domain lacking the metal-chelating residues

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“…Yet other co-chaperones are able to associate with the chaperone/ CHIP complex and then modulate CHIP-mediated degradation in the formed ternary complex (Figure 2). Among these regulators are the Hsc/Hsp70 co-chaperones BAG-2 and HspBP1, which both act as degradation inhibitors (Alberti et al, 2004;Arndt et al, 2005;Dai et al, 2005). They inhibit the ubiquitin ligase activity of CHIP in the formed chaperone/co-chaperone complex, and the resultant attenuation of CAP was shown to be important for the maturation of the cystic fibrosis ion channel CFTR (Alberti et al, 2004;Arndt et al, 2005).…”

Section: Figurementioning

confidence: 99%

Chaperone-assisted degradation: multiple paths to destruction

Kettern

Dreiseidler

Tawo³

et al. 2010

Biological Chemistry

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Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP ( haperone-ssisted roteasomal degradac a p tion), CASA ( haperone-ssisted elective utophagy), and c a s a CMA ( haperone-ediated utophagy). Within these pathc m a ways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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BAG-2 Acts as an Inhibitor of the Chaperone-associated Ubiquitin Ligase CHIP

Cited by 173 publications

References 45 publications

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Chaperone-assisted degradation: multiple paths to destruction

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