The Cochaperone HspBP1 Inhibits the CHIP Ubiquitin Ligase and Stimulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

Alberti, Simon; Böhse, Karsten; Arndt, Verena; Schmitz, Anton; Höhfeld, Jörg

doi:10.1091/mbc.e04-04-0293

Cited by 167 publications

(153 citation statements)

References 36 publications

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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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Section: Discussionmentioning

confidence: 99%

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

Fofo²,

et al. 2013

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“…For example, it has been shown that HspBP1 is involved in the control of proteasomal activity by inhibition of CHIP ubiquitin ligase when it is complexed with Hsp70 (30). Recently it has been found that binding of HspBP1 to Hsp70 prevents inhibition of cathepsin-dependent death of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

The Heat Shock-binding Protein (HspBP1) Protects Cells against the Cytotoxic Action of the Tag7-Hsp70 Complex

Yashin

Dukhanina

Kabanova

et al. 2011

Journal of Biological Chemistry

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Heat shock-binding protein HspBP1 is a member of the Hsp70 co-chaperone family. The interaction between HspBP1 and the ATPase domain of the major heat shock protein Hsp70 up-regulates nucleotide exchange and reduces the affinity between Hsp70 and the peptide in its peptide-binding site. Previously we have shown that Tag7 (also known as peptidoglycan recognition protein PGRP-S), an innate immunity protein, interacts with Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against some tumor cell lines. This complex can be produced in cytotoxic lymphocytes and released during interaction with tumor cells. Here the effect of HspBP1 on the cytotoxic activity of the Tag7-Hsp70 complex was examined. HspBP1 could bind not only to Hsp70, but also to Tag7. This interaction eliminated the cytotoxic activity of Tag7-Hsp70 complex and decreased the ATP concentration required to dissociate Tag7 from the peptide-binding site of Hsp70. Moreover, HspBP1 inhibited the cytotoxic activity of the Tag7-Hsp70 complex secreted by lymphocytes. HspBP1 was detected in cytotoxic CD8؉ lymphocytes. This protein was released simultaneously with Tag7-Hsp70 during interaction of these lymphocytes with tumor cells. The simultaneous secretion of the cytotoxic complex with its inhibitor could be a mechanism protecting normal cells from the cytotoxic effect of this complex.

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“…HspBP1 is the least efficient as an NEF and is inhibitory of Hsc70 refolding function under all conditions tested. Biologically, HspBP1 promotes the degradation of proteins and blocks the anti-apoptotic function of stress-induced Hsp70 (44,45). These functions are consistent with HspBP1 acting as an inhibitor of Hsc70.…”

Section: Discussionmentioning

confidence: 99%

Functional Divergence between Co-chaperones of Hsc70

Tzankov

Wong

Shi

et al. 2008

Journal of Biological Chemistry

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The ATPase cycle of the chaperone Hsc70 is regulated by co-chaperones; Hsp40/DnaJ-related proteins stimulate ATP hydrolysis by Hsc70 and can bind unfolded polypeptides themselves. Conversely, various nucleotide exchange factors (NEFs) stimulate ADP-ATP exchange by Hsc70. We analyzed the purified Hsp40-related co-chaperones DJA1 (Hdj2) and DJA2 (Hdj3) and found that they had a distinct pattern of binding to a range of polypeptides. DJA2 alone could stimulate Hsc70-mediated refolding of luciferase in the absence of NEF, whereas DJA1 was much less active. The addition of the Bag1 NEF increased refolding by Hsc70 and DJA2, as did the newly characterized NEF Hsp110, but each NEF had a different optimal concentration ratio to Hsc70. Notably, the NEF HspBP1 could not increase refolding by Hsc70 and DJA2 at any concentration, and none of the NEFs improved the refolding activity with DJA1. Instead, DJA1 was inhibitory of refolding with DJA2 and Hsc70. All combinations of DJA1 or DJA2 with the three NEFs stimulated the Hsc70 ATPase rate, although Hsp110 became less effective with increasing concentrations. A chimeric DJA2 having its Hsc70-stimulatory J domain replaced with that of DJA1 was functional for polypeptide binding and ATPase stimulation of Hsc70. However, it could not support efficient Hsc70-mediated refolding and also inhibited refolding with DJA2 and Hsc70. These results suggest a more complex model of Hsc70 mechanism than has been previously thought, with notable functional divergence between Hsc70 co-chaperones.The Hsp70 family of proteins are ATP-dependent molecular chaperones that assist the folding of polypeptides. Hsp70 chaperones have a typical structure divided into ATPase and substrate-binding domains that work in an ATP-driven substrate binding cycle. The mechanism of Hsp70 proteins has been well established in studies of the Escherichia coli homolog DnaK. In the ATP-bound state, an Hsp70 chaperone has low affinity for unfolded polypeptide. After hydrolysis of ATP, Hsp70 in the ADP-bound state binds substrate with high affinity. Exchange of ADP for ATP then reverts Hsp70 to its low polypeptide affinity state. Conversion of an Hsp70 between these two nucleotide states is controlled by different co-chaperone proteins. The Hsp40/DnaJ-related co-chaperones, including E. coli DnaJ, contain J domains that stimulate ATP hydrolysis by Hsp70, and consequently substrate binding. Nucleotide exchange factors (NEFs), 2 such as GrpE in E. coli, trigger the dissociation of bound ADP from Hsp70 to allow the binding of ATP, resetting the cycle. The principles of this mechanism appear to be conserved in Hsp70 chaperones, including the major cytosolic form in humans, Hsc70 (HSPA8) (1, 2).The DnaJ-related co-chaperones are also conserved between species. Type 1 J domain co-chaperones are homologous to DnaJ throughout their sequence and have the same domain architecture. Following their N-terminal J domains, they contain a linker sequence, zinc finger and central regions, and a C-terminal homodimerization region. Unfolde...

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The Cochaperone HspBP1 Inhibits the CHIP Ubiquitin Ligase and Stimulates the Maturation of the Cystic Fibrosis Transmembrane Conductance Regulator

Cited by 167 publications

References 36 publications

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

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

The Heat Shock-binding Protein (HspBP1) Protects Cells against the Cytotoxic Action of the Tag7-Hsp70 Complex

Functional Divergence between Co-chaperones of Hsc70

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