BAG3 mediates chaperone‐based aggresome‐targeting and selective autophagy of misfolded proteins

Gamerdinger, Martin; Kaya, A Murat; Wolfrum, Uwe; Clement, Albrecht M.; Behl, Christian

doi:10.1038/embor.2010.203

Cited by 319 publications

(368 citation statements)

References 14 publications

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“…8 Also, BAG3 has recently been reported to mediate selective autophagy of misfolded proteins independently of substrate ubiquitination. 23 The novelty of our study resides in particular in the identification of BAG3 as a key mediator of an inducible, compensatory PQC pathway to support RMS cell survival in response to concomitant blockade of basal PQC pathways by ST80/Bortezomib cotreatment. Concomitant pharmacological inhibition of the proteasome and HDAC6 has recently been suggested to be superior to treatment with proteasome inhibitors alone to trigger cell death in cancer cells, as inefficient degradation by one of the two major constitutive pathways for protein turnover is often compensated by increased protein degradation by the other system.…”

Section: Discussionmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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Simultaneous inhibition of the two major constitutive protein quality control (PQC) pathways, that is, the ubiquitin-proteasome system (UPS) and the aggresome-autophagy system, has been suggested as a promising strategy to trigger cell death in cancer cells. However, we observed that one third of rhabdomyosarcoma (RMS) cells survives parallel inhibition of the UPS by Bortezomib and the aggresome-autophagy pathway by the cytoplasmic histone deacetylase 6 inhibitor ST80, and is able to regrow upon drug removal, thus pointing to the induction of compensatory pathways. Here, we identify Bcl-2-associated athanogene 3 (BAG3) as a critical mediator of inducible resistance in surviving cells after concomitant blockage of constitutive PQC pathways by mitigating ST80/Bortezomib-triggered proteotoxicity via selective autophagy. ST80/Bortezomib cotreatment upregulates BAG3 mRNA and protein levels in surviving cells in addition to triggering the accumulation of insoluble protein aggregates. Intriguingly, knockdown of BAG3 by RNA interference severely impairs clearance of protein aggregates, significantly increases cell death and reduces longterm survival and clonogenic growth during recovery after ST80/Bortezomib cotreatment. Similarly, inhibition of autophagy by inducible autophagy-related protein 7 knockdown prevents removal of protein aggregates and cell regrowth during recovery after ST80/Bortezomib cotreatment. Also, the inhibition of lysosomal degradation using the V-ATPase pump inhibitor Bafilomycin A1 enhances accumulation of protein aggregates, and completely abolishes regrowth after Bortezomib/ST80-induced proteotoxic stress. By identifying BAG3 as a key mediator of inducible resistance by mitigating proteotoxicity via selective autophagy after inhibition of constitutive PQC systems, our study provides new insights into the regulation of PQC pathways in cancer cells and identifies new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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“…1C). Indeed, the plasmids previously described to overexpress the proline-rich region and BAG domain of BAG3 (ppxxpBAG) or BAG3 without its BAG domain (pBAGD), 14 also increased total LC3B protein levels (Fig. 1D).…”

Section: Resultsmentioning

confidence: 99%

“…11,13,14,20 BAG3 acts by selectively directing proteins to aggresomes, where autophagy has high activity. 14 However, the mechanism that BAG3 uses to activate the autophagy signaling remains unknown.…”

Section: Resultsmentioning

confidence: 99%

“…10 In recent studies, BAG3 was shown to control the selective degradation of misfolded proteins by autophagy, including polyQ-expanded HTT (huntingtin) and mutant SOD1 (superoxide dismutase 1, soluble). [11][12][13][14] The mechanism involves BAG3 association with dynein to transport misfolded proteins to the aggresomes, facilitating their clearance by autophagy. 14 Besides the role in folding and degradation of proteins, recently the role of the HSP70 chaperones in the regulation of the translation of proteins has been described.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] The mechanism involves BAG3 association with dynein to transport misfolded proteins to the aggresomes, facilitating their clearance by autophagy. 14 Besides the role in folding and degradation of proteins, recently the role of the HSP70 chaperones in the regulation of the translation of proteins has been described. HSP70 is associated with the nascent polypeptide, assisting in the folding of newly synthesized proteins and acting as sensor for downstream folding conditions.…”

Section: Introductionmentioning

confidence: 99%

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BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism

et al. 2016

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Autophagy is mainly regulated by post-translational and lipid modifications of ATG proteins. In some scenarios, the induction of autophagy is accompanied by increased levels of certain ATG mRNAs such as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the regulation of ATG protein synthesis at the translational level. The cochaperone of the HSP70 system BAG3 (BCL2-associated athanogene 3) has been associated to LC3B lipidation through an unknown mechanism. In the present work, we studied how BAG3 controls autophagy in HeLa and HEK293 cells. Our results showed that BAG3 regulates the basal amount of total cellular LC3B protein by controlling its mRNA translation. This effect was apparently specific to LC3B because other ATG protein levels were not affected. BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome inhibition. We concluded that BAG3 maintains the basal amount of LC3B protein by controlling the translation of its mRNA in HeLa and HEK293 cells.

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Dissection of ubiquitinated protein degradation by basal autophagy

2017

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Basal autophagy plays an essential role as a protein quality control system. Although it has been demonstrated that the loss of autophagy results in the accumulation of ubiquitin‐positive aggregates and the development of neurodegenerative diseases, the precise autophagy substrate(s) remain unclear. Here, we determined whether ubiquitinated proteins are direct substrates for basal autophagy using a fluorescent ratiometric probe for ubiquitin. We show that the degradation of polyubiquitinated proteins is not dependent on basal autophagy. Although ubiquitin‐positive aggregates are observed in autophagy knockout cultured cells, the aggregates consist of soluble and mobile polyubiquitinated proteins, which are trapped by p62 without an increase in the total amount of ubiquitinated proteins. These results suggest that ubiquitinated proteins are not major targets for basal autophagy.

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BAG3 mediates chaperone‐based aggresome‐targeting and selective autophagy of misfolded proteins

Cited by 319 publications

References 14 publications

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism

Dissection of ubiquitinated protein degradation by basal autophagy

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