The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins

Wolfe, Katie J.; Ren, Hong Yu; Trepte, Philipp; Cyr, Douglas M.

doi:10.1091/mbc.e13-06-0315

Cited by 61 publications

(71 citation statements)

References 72 publications

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“…Toxic Htt103Q aggregates consisted of many small puncta, whereas protective Htt103Q aggregates consisted of large foci at the IPOD. In another report, the sequestration of Htt103Q into Sti1 foci, a juxtanuclear site distinct from the JUNQ and IPOD, also reduced toxicity (36). Thus, irrespective of their subcellular localization, the formation of large Htt103Q foci seems to be protective against toxicity.…”

Section: Discussionmentioning

confidence: 90%

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Kayatekin

Matlack

Hesse

et al. 2014

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

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Expansions of preexisting polyglutamine (polyQ) tracts in at least nine different proteins cause devastating neurodegenerative diseases. There are many unique features to these pathologies, but there must also be unifying mechanisms underlying polyQ toxicity. Using a polyQ-expanded fragment of huntingtin exon-1 (Htt103Q), the causal protein in Huntington disease, we and others have created tractable models for investigating polyQ toxicity in yeast cells. These models recapitulate key pathological features of human diseases and provide access to an unrivalled genetic toolbox. To identify toxicity modifiers, we performed an unbiased overexpression screen of virtually every protein encoded by the yeast genome. Surprisingly, there was no overlap between our modifiers and those from a conceptually identical screen reported recently, a discrepancy we attribute to an artifact of their overexpression plasmid. The suppressors of Htt103Q toxicity recovered in our screen were strongly enriched for glutamine-and asparagine-rich prion-like proteins. Separated from the rest of the protein, the prion-like sequences of these proteins were themselves potent suppressors of polyQ-expanded huntingtin exon-1 toxicity, in both yeast and human cells. Replacing the glutamines in these sequences with asparagines abolished suppression and converted them to enhancers of toxicity. Replacing asparagines with glutamines created stronger suppressors. The suppressors (but not the enhancers) coaggregated with Htt103Q, forming large foci at the insoluble protein deposit in which proteins were highly immobile. Cells possessing foci had fewer (if any) small diffusible oligomers of Htt103Q. Until such foci were lost, cells were protected from death. We discuss the therapeutic implications of these findings.protein misfolding | prions P rotein misfolding and aggregation underlie many neurodegenerative diseases. The causes of protein misfolding are numerous and include single amino acid changes and expansions of amino acid repeats. Polyglutamine (polyQ) expansions are an infamous example of the latter and are responsible for at least nine neurodegenerative conditions, including Huntington disease (HD). In most of these diseases the polyQ-expanded protein is expressed throughout the body, but tissue damage is restricted to the nervous system and, often, to a subset of cells depending on the causal protein. Thus, there are important cell type-specific determinants of toxicity, and these are specific to particular proteins. Despite these differences, disease severity is tightly linked to the number of glutamines. Progressively earlier onset occurs as the number of glutamines increases beyond a critical threshold of ∼35-45 residues (1). Moreover, in all cases, pathology is associated with misfolded forms of the polyQ-expanded protein.Thus, common features that arise from the expansions and result from shared aspects of polyQ-driven protein misfolding must contribute to pathology. Given the diverse nature of both the proteins bearing the polyQ tract and t...

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Section: Discussionmentioning

confidence: 90%

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Kayatekin

Matlack

Hesse

et al. 2014

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

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“…Besides being associated with aggregates, Hsp110 was enriched in a manner correlating with the relative toxicity of the aggregates when overexpressed in a human cell lineage (Olzscha et al 2011). Other proteins also seem to collaborate with Hsp110 in a system that recovers protein aggregates in the cell, including HOP, and small Hsps (Rampelt et al 2012, Mattoo et al 2013, Torrente and Shorter 2014, Wolfe et al 2013. By overexpressing amyloid-like aggregates in a human cell model, Olzscha et al (2011) showed that Hsc70 and its co-chaperones Hsp110, Hsp40/ Hdj1/2, and Bag2 associated with the aggregates.…”

Section: Shifting Paradigms On Aggregate Resolubilization In Metazoansmentioning

confidence: 99%

Disaggregases, molecular chaperones that resolubilize protein aggregates

Mokry

Abrahão

Ramos

2015

An. Acad. Bras. Ciênc.

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The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

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“…Cytoprotection may involve several mutually non-exclusive effects. First, controlled deposition of soluble misfolded proteins can reduce their cytotoxicity (Arrasate et al 2004;Cheng et al 2007;Cohen et al 2006;Cohen et al 2009;Walther et al 2015;Wolfe et al 2013). Second, it might prevent exhaustion of the protein quality control machinery during protein folding stress, by confining the sticky surfaces of misfolded proteins.…”

Section: Sequestration Of Misfolded Proteins As Protective Strategymentioning

confidence: 99%

Role of sHsps in organizing cytosolic protein aggregation and disaggregation

Mogk

Bukau

2017

Cell Stress and Chaperones

104

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Small heat shock proteins (sHsps) exhibit an ATPindependent chaperone activity to prevent the aggregation of misfolded proteins in vitro. The seemingly conflicting presence of sHsps in insoluble protein aggregates in cells obstructs a precise definition of sHsp function in proteostasis networks. Recent findings specify sHsp activities in protein quality control systems. The sHsps of yeast, Hsp42 and Hsp26, interact with early unfolding intermediates of substrates, keeping them in a ready-to-refold conformation close to the native state. This activity facilitates substrate refolding by ATPdependent Hsp70-Hsp100 disaggregating chaperones. Hsp42 can actively sequester misfolded proteins and promote their deposition at specific cellular sites. This aggregase activity represents a cytoprotective protein quality control strategy. The aggregase function of Hsp42 controls the formation of cytosolic aggregates (CytoQs) under diverse stress regimes and can be reconstituted in vitro, demonstrating that Hsp42 is necessary and sufficient to promote protein aggregation. Substrates sequestered at CytoQs can be dissociated by Hsp70-Hsp100 disaggregases for subsequent triage between refolding and degradation pathways or are targeted for destruction by selective autophagy termed proteophagy.

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The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins

Cited by 61 publications

References 72 publications

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1

Disaggregases, molecular chaperones that resolubilize protein aggregates

Role of sHsps in organizing cytosolic protein aggregation and disaggregation

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