Sequestration of Sup35 by Aggregates of huntingtin Fragments Causes Toxicity of [PSI+] Yeast

Zhao, Xiaohong; Park, Yang-Nim; Todor, Horia; Moomau, Christine A.; Masison, Daniel C.; Eisenberg, Evan; Greene, Lois E.

doi:10.1074/jbc.m111.287748

Cited by 23 publications

(27 citation statements)

References 30 publications

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“…As a result, the association of molecular chaperones of the Hsp70 and Hsp90 systems with the polyQ aggregates was enhanced, and their ability to sequester nuclear proteins was strongly reduced. Protein sequestration into aggregates may lead to an impairment of multiple key cellular pathways and is considered an important mechanism of aggregate toxicity (7,9,10,32,50,(53)(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Ripaud¹,

Chumakova²,

Antonin³

et al. 2014

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

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Expansion of a poly-glutamine (polyQ) repeat in a group of functionally unrelated proteins is the cause of several inherited neurodegenerative disorders, including Huntington's disease. The polyQ length-dependent aggregation and toxicity of these disease proteins can be reproduced in Saccharomyces cerevisiae. This system allowed us to screen for genes that when overexpressed reduce the toxic effects of an N-terminal fragment of mutant huntingtin with 103 Q. Surprisingly, among the identified suppressors were three proteins with Q-rich, prion-like domains (PrDs): glycine threonine serine repeat protein (Gts1p), nuclear polyadenylated RNA-binding protein 3, and minichromosome maintenance protein 1. Overexpression of the PrD of Gts1p, containing an imperfect 28 residue glutamine-alanine repeat, was sufficient for suppression of toxicity. Association with this discontinuous polyQ domain did not prevent 103Q aggregation, but altered the physical properties of the aggregates, most likely early in the assembly pathway, as reflected in their increased SDS solubility. Molecular simulations suggested that Gts1p arrests the aggregation of polyQ molecules at the level of nonfibrillar species, acting as a cap that destabilizes intermediates on path to form large fibrils. Quantitative proteomic analysis of polyQ interactors showed that expression of Gts1p reduced the interaction between polyQ and other prion-like proteins, and enhanced the association of molecular chaperones with the aggregates. These findings demonstrate that short, Q-rich peptides are able to shield the interactive surfaces of toxic forms of polyQ proteins and direct them into nontoxic aggregates.protein aggregation | protein misfolding | neurodegeneration | prion | polyglutamine proteins

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Section: Discussionmentioning

confidence: 99%

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Ripaud¹,

Chumakova²,

Antonin³

et al. 2014

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

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“…On the other hand, some studies have revealed that the sequestration is mediated by coaggregation of polyQ tracts (53)(54)(55). Cooperative polyQ-polyQ interactions also prompt aggregation of the polyQ proteins.…”

Section: Specific Interaction Is Vital For the Sequestration Of Usp22 Bymentioning

confidence: 99%

Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex

Liu

et al. 2015

Journal of Biological Chemistry

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Background: Expansion of the polyQ tract in ataxin 7 is the main pathology of SCA7. Results: The aggregates formed by polyQ-expanded ataxin 7 sequester USP22 through specific interactions. Conclusion: Sequestration of USP22 impairs its deubiquitinating function in the SAGA complex. Significance: This provides evidence for the hijacking model in which specific sequestration leads to cytotoxicity and neurodegeneration.

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“…For example, polyQ-expanded Htt aggregation and its associated toxicity are strongly enhanced by overexpression of polyQN-rich proteins or by the presence of the endogenous yeast prions [ RNQ + ] and [ PSI + ] (Meriin et al, 2002, Duennwald et al, 2006a, Kochneva-Pervukhova et al, 2012, Gong et al, 2012, Zhao et al, 2012, Gokhale et al, 2005, Giorgini et al, 2005), and this enhancement corresponds to co-localization of the aggregating proteins (Meriin et al, 2003, Duennwald et al, 2006a, Gong et al, 2012). Given the ability of polyQ-expanded Htt to induce aggregation of Sup35 (Kochneva-Pervukhova et al, 2012, Urakov et al, 2010) and the essential function of Sup35 in translation termination (Ter-Avanesyan et al, 1993), several groups explored the possibility of Sup35 sequestration as a mechanism for Htt toxicity in yeast (Gong et al, 2012, Kochneva-Pervukhova et al, 2012, Zhao et al, 2012). In the presence of [ RNQ + ] alone, polyQ-expanded Htt clearly induced aggregation of Sup35 (Gong et al, 2012, Kochneva-Pervukhova et al, 2012), but expression of the Sup35 functional domain was efficient in suppressing toxicity in one study (Kochneva-Pervukhova et al, 2012) but not in another (Gong et al, 2012).…”

Section: Polyq Toxicity In Yeastmentioning

confidence: 99%

“…In the presence of [ RNQ + ] alone, polyQ-expanded Htt clearly induced aggregation of Sup35 (Gong et al, 2012, Kochneva-Pervukhova et al, 2012), but expression of the Sup35 functional domain was efficient in suppressing toxicity in one study (Kochneva-Pervukhova et al, 2012) but not in another (Gong et al, 2012). However, in the presence of both [ RNQ + ] and [ PSI + ], the toxicity of polyQ-expanded Htt is efficiently suppressed by expression of the functional domain of Sup35 (Gong et al, 2012, Zhao et al, 2012). Thus, while either type of aggregate alone is benign, the combination of polyQ and prion aggregates creates an imbalance presumably between the aggregation assembly pathway and cellular protein quality control pathways that promotes sequestration of Sup35 and thereby toxicity (Figure 1b).…”

Section: Polyq Toxicity In Yeastmentioning

confidence: 99%

“…Intriguingly, while an FHttQ103 variant containing the proline-rich region (FHttQ103P) is not toxic in a [ RNQ + ] strain (Duennwald et al, 2006a, Wang et al, 2009), this protein is toxic in a [ RNQ + ] [ PSI + ] strain, where the pool of functional Sup35 is already depleted (Gong et al, 2012, Zhao et al, 2012). Thus, although FHttQ103 can also induce toxicity through the sequestration of actin assembly proteins (Meriin et al, 2003), the synthetic interaction with [ PSI + ] suggests that FHttQ103 toxicity, like that of FHttQ103P, can arise through the sequestration of Sup35 but that the latter is less efficient in inactivating Sup35.…”

Section: Aggregate Dynamicsmentioning

confidence: 99%

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Defining the limits: Protein aggregation and toxicityin vivo

Holmes

Klaips

Serio

2014

Critical Reviews in Biochemistry and Molecular Biology

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The proper folding of proteins to their functional forms is essential to cellular homeostasis. Perhaps not surprisingly, cells have evolved multiple pathways, some overlapping and others complementary, to resolve misfolded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic, and/or stochastic events, protein misfolding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington’s Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein misfolding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them, and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.

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Sequestration of Sup35 by Aggregates of huntingtin Fragments Causes Toxicity of [PSI+] Yeast

Cited by 23 publications

References 30 publications

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex

Defining the limits: Protein aggregation and toxicityin vivo

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