Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel–Lindau tumor suppressor protein

Goff, Xavier Le; Chesnel, Franck; Delalande, Olivier; Couturier, Antoine; Dreano, Stéphane; Goff, Cathy Le; Vigneau, Cécile; Arlot‐Bonnemains, Yannick

doi:10.1242/jcs.184846

Cited by 13 publications

(11 citation statements)

References 36 publications

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“…Various conditions, such as cellular stress, mutation, or defects during protein synthesis, may cause partial denaturation of cell proteins. Such proteins are either shielded from aggregation and refolded to the native state by molecular chaperones (Hartl and Hayer-Hartl 2009) or targeted for degradation via the ubiquitin-proteasome system (UPS) (Cyr et al 2002;Esser et al 2004;Kettern et al 2010;Le Goff et al 2016;McClellan et al 2005;Powers et al 2009;Wiederkehr et al 2002). To mount this, stress response involves activation of the heat shock factor (HSF) transcriptional regulator, Hsf1, which drives the synthesis of molecular chaperones and other stress-relieving proteins (Zobeck et al 2010).…”

Section: Introductionmentioning

confidence: 99%

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

Poulsen

Kampmeyer

Kriegenburg

et al. 2017

Cell Stress and Chaperones

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As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis of molecular chaperones and other stress-relieving proteins. Here, we show that the fission yeast Schizosaccharomyces pombe orthologues of human BAG-1, Bag101, and Bag102, are Hsp70 co-chaperones that associate with 26S proteasomes. Only a subgroup of Hsp70-type chaperones, including Ssa1, Ssa2, and Sks2, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused by triggering Hsp70 to release and activate the Hsf1 transcription factor. Accordingly, the bag101-linked growth defect is alleviated in strains containing a reduced amount of Hsf1 but aggravated in hsp70 deletion strains. In conclusion, we propose that the fission yeast UBL/BAG proteins release Hsf1 from Hsp70, leading to constitutive Hsf1 activation and growth defects.

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Section: Introductionmentioning

confidence: 99%

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

Poulsen

Kampmeyer

Kriegenburg

et al. 2017

Cell Stress and Chaperones

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“…Because misfolded proteins tend to form toxic aggregates with other cell proteins, the accumulation of misfolded proteins represents a considerable danger to cells. To cope with such harmful protein variants, cells have evolved efficient protein quality control (PQC) 3 mechanisms that function to clear the cell of misfolded proteins (17)(18)(19). Typically, these rely on molecular chaperones that capture misfolded proteins and either refold them or guide them to degradation via the ubiquitin-proteasome system (UPS).…”

mentioning

confidence: 99%

The exocyst subunit Sec3 is regulated by a protein quality control pathway

Kampmeyer

Karakostova

Schenstrøm

et al. 2017

Journal of Biological Chemistry

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Exocytosis involves fusion of secretory vesicles with the plasma membrane, thereby delivering membrane proteins to the cell surface and releasing material into the extracellular space. The tethering of the secretory vesicles before membrane fusion is mediated by the exocyst, an essential phylogenetically conserved octameric protein complex. Exocyst biogenesis is regulated by several processes, but the mechanisms by which the exocyst is degraded are unknown. Here, to unravel the components of the exocyst degradation pathway, we screened for extragenic suppressors of a temperature-sensitive fission yeast strain mutated in the exocyst subunit Sec3 (). One of the suppressing DNAs encoded a truncated dominant-negative variant of the 26S proteasome subunit, Rpt2, indicating that exocyst degradation is controlled by the ubiquitin-proteasome system. The temperature-dependent growth defect of the strain was gene dosage-dependent and suppressed by blocking the proteasome, Hsp70-type molecular chaperones, the Pib1 E3 ubiquitin-protein ligase, and the deubiquitylating enzyme Ubp3. Moreover, defects in cell septation, exocytosis, and endocytosis in mutant strains were similarly alleviated by mutation of components in this pathway. We also found that, particularly under stress conditions, wild-type Sec3 degradation is regulated by Pib1 and the 26S proteasome. In conclusion, our results suggest that a cytosolic protein quality control pathway monitors folding and proteasome-dependent turnover of an exocyst subunit and, thereby, controls exocytosis in fission yeast.

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“…PFDN3 is necessary to maintain the stability of Von Hippel-Lindau (VHL). 33 Known as Von Hippel-Lindau binding protein 1 (VBP1), 34 PFDN3 interacts with VHL protein to form a complex that can promote the stability of microtubules and regulate protein stability. 35 VHL is a tumor suppressor protein, which can interact with c-CPN to mediate the folding and assembly of tumor suppressor complexes.…”

Section: Pfdn3 and Protein Degradationmentioning

confidence: 99%

<p>The Role of Prefoldin and Its Subunits in Tumors and Their Application Prospects in Nanomedicine</p>

Mo¹,

Zhao²,

Tian³

et al. 2020

CMAR

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Prefoldin (PFDN) is a hexameric chaperone complex that is widely found in eukaryotes and archaea and consists of six different subunits (PFDN1-6). Its main function is to transfer actin and tubulin monomers to the eukaryotic cell cytoplasmic chaperone protein (c-CPN) specific binding during the assembly of the cytoskeleton, to stabilize the newly synthesized peptides so that they can be folded correctly. The current study found that each subunit of PFDN has different functions, which are closely related to the occurrence, development and prognosis of tumors. However, the best characteristics of each subunit have not been fully affirmed. The connection between research and tumors can change the understanding of PFDN and further extend its potential prognostic role and structural function to cancer research and clinical practice. This article mainly reviews the role of canonical PFDN and its subunits in tumors and other diseases, and discusses the potential prospects of the unique structure and function of PFDN in nanomedicine.

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Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel–Lindau tumor suppressor protein

Cited by 13 publications

References 36 publications

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

The exocyst subunit Sec3 is regulated by a protein quality control pathway

<p>The Role of Prefoldin and Its Subunits in Tumors and Their Application Prospects in Nanomedicine</p>

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