Differential contributions of the proteasome, autophagy, and chaperones to the clearance of arsenite-induced protein aggregates in yeast

Hua, Sansan; Kłosowska, Agnieszka; Rodrigues, Joana Isabel; Petelski, Gabriel; Esquembre, Lidia A.; Lorentzon, Emma; Olsen, Lars Folke; Liberek, Krzysztof; Tamás, Markus J.

doi:10.1016/j.jbc.2022.102680

Cited by 3 publications

(28 citation statements)

References 70 publications

(154 reference statements)

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“…Chaperone-mediated refolding of luciferase was also inhibited by As(III), but its impact was greater on the substrate than on the chaperone system [ 175 ]. Importantly, the defect in chaperone-mediated refolding of green fluorescent protein was abrogated in a cysteine-free version of the substrate protein [ 176 ], providing strong evidence that As(III) directly modifies cysteine residues in non-native target proteins. Together, these in vitro studies established that As(III) can inhibit the formation of the native protein fold by forming complexes with cysteine side chains (Fig.…”

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

“…Thus, it is not clear whether As(III) primarily affects TRiC/CCT activity or the folding substrate. Interestingly, the purified yeast Hsp70 and bichaperone Hsp70–Hsp104 systems were inhibited by As(III) to similar degrees as the bacterial Hsp70 system [ 175 , 176 ]. However, instead of inhibiting the yeast chaperones, As(III) impaired protein disaggregation by modifying the structure of the aggregates, thereby preventing efficient binding of the chaperones to the aggregate [ 176 ].…”

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

“…Interestingly, the purified yeast Hsp70 and bichaperone Hsp70–Hsp104 systems were inhibited by As(III) to similar degrees as the bacterial Hsp70 system [ 175 , 176 ]. However, instead of inhibiting the yeast chaperones, As(III) impaired protein disaggregation by modifying the structure of the aggregates, thereby preventing efficient binding of the chaperones to the aggregate [ 176 ]. One way As(III) could affect aggregate structure is by acting as an intermolecular crosslinker between two or three polypeptide chains leading to the formation of heterodimers and trimers [ 32 , 36 , 176 ].…”

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

“…However, instead of inhibiting the yeast chaperones, As(III) impaired protein disaggregation by modifying the structure of the aggregates, thereby preventing efficient binding of the chaperones to the aggregate [ 176 ]. One way As(III) could affect aggregate structure is by acting as an intermolecular crosslinker between two or three polypeptide chains leading to the formation of heterodimers and trimers [ 32 , 36 , 176 ]. Possibly, the observed changes of aggregate properties in the presence of As(III) [ 176 ] may not only reduce chaperone binding but might also affect aggregate processing by other PQC systems.…”

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

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Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Wysocki,

Rodrigues,

Litwin

et al. 2023

Cell. Mol. Life Sci.

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Arsenic and antimony are metalloids with profound effects on biological systems and human health. Both elements are toxic to cells and organisms, and exposure is associated with several pathological conditions including cancer and neurodegenerative disorders. At the same time, arsenic- and antimony-containing compounds are used in the treatment of multiple diseases. Although these metalloids can both cause and cure disease, their modes of molecular action are incompletely understood. The past decades have seen major advances in our understanding of arsenic and antimony toxicity, emphasizing genotoxicity and proteotoxicity as key contributors to pathogenesis. In this review, we highlight mechanisms by which arsenic and antimony cause toxicity, focusing on their genotoxic and proteotoxic effects. The mechanisms used by cells to maintain proteostasis during metalloid exposure are also described. Furthermore, we address how metalloid-induced proteotoxicity may promote neurodegenerative disease and how genotoxicity and proteotoxicity may be interrelated and together contribute to proteinopathies. A deeper understanding of cellular toxicity and response mechanisms and their links to pathogenesis may promote the development of strategies for both disease prevention and treatment.

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Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

Section: How Arsenic Causes Proteotoxicitymentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Wysocki,

Rodrigues,

Litwin

et al. 2023

Cell. Mol. Life Sci.

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“…As (III) inhibits protein folding primarily by binding to cysteine residues in non-native proteins [35,[40][41][42]. Chaperone-assisted folding or disaggregation may also be affected, either by direct binding to the chaperone or by affecting aggregate structure such that efficient binding of the chaperone to the aggregate is impaired [37,38,42,43]. Additionally, As(III)-misfolded proteins can seed the misfolding and aggregation of other proteins that have not encountered the metalloid [37].…”

mentioning

confidence: 99%

Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

et al. 2023

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Arsenite causes proteotoxicity by targeting nascent proteins for misfolding and aggregation. Here, we assessed how selected yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress. Loss of the ribosome‐associated chaperones Zuo1, Ssz1, and Ssb1/Ssb2 reduced global translation and protein aggregation, and increased arsenite resistance. Loss of cytosolic GimC/prefoldin function led to defective aggregate clearance and arsenite sensitivity. Arsenite did not induce ribosomal stalling or impair ribosome quality control, and ribosome‐associated ubiquitin ligases contributed little to proteostasis. Instead, the cytosolic ubiquitin ligase Rsp5 was important for aggregate clearance and resistance. Our study suggests that damage prevention, by decreased aggregate formation, and damage elimination, by enhanced aggregate clearance, are important protective mechanisms that maintain proteostasis during arsenite stress.

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Chaperone regulation of biomolecular condensates

Bard,

Drummond

2024

Front. Biophys.

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Biomolecular condensation allows for the dynamic organization of molecules in time and space. Condensate formation is regulated through many mechanisms including the action of molecular chaperones. While molecular chaperones have long been viewed through the lens of their roles in protein folding, misfolding, and quality control, their ability to manipulate protein-protein interactions is increasingly recognized to play a major role in the precise control of condensate biology. In this review we highlight recent studies investigating the roles of canonical and non-canonical chaperones in regulating condensate formation, material state, and dispersal. We discuss the broadening of longstanding conceptions of chaperone functions to include condensate regulation, and the discovery of previously unappreciated chaperone activities in well-known proteins. We close by considering the biological activities being uncovered during the ongoing upheaval at the boundary between chaperone biology and biomolecular condensation.

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Differential contributions of the proteasome, autophagy, and chaperones to the clearance of arsenite-induced protein aggregates in yeast

Cited by 3 publications

References 70 publications

Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates

Chaperone regulation of biomolecular condensates

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