Disaggregases, molecular chaperones that resolubilize protein aggregates

Mokry, David Z.; Abrahão, Josielle; Ramos, Carlos H.I.

doi:10.1590/0001-3765201520140671

Cited by 25 publications

(30 citation statements)

References 162 publications

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“…In general, protein aggregates are associated with molecular chaperones and heat shock proteins that can extricate protein monomers from the aggregates and refold them into their native structures [12,13]. One of the most well-studied heat shock proteins in yeasts is Hsp104, an ATP-dependent disaggregase that is often used as a molecular marker of protein aggregation in both S .…”

Section: Resultsmentioning

confidence: 99%

Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe

Nakaoka

Wakamoto

2017

PLoS Biol

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Replicative aging has been demonstrated in asymmetrically dividing unicellular organisms, seemingly caused by unequal damage partitioning. Although asymmetric segregation and inheritance of potential aging factors also occur in symmetrically dividing species, it nevertheless remains controversial whether this results in aging. Based on large-scale single-cell lineage data obtained by time-lapse microscopy with a microfluidic device, in this report, we demonstrate the absence of replicative aging in old-pole cell lineages of Schizosaccharomyces pombe cultured under constant favorable conditions. By monitoring more than 1,500 cell lineages in 7 different culture conditions, we showed that both cell division and death rates are remarkably constant for at least 50–80 generations. Our measurements revealed that the death rate per cellular generation increases with the division rate, pointing to a physiological trade-off with fast growth under balanced growth conditions. We also observed the formation and inheritance of Hsp104-associated protein aggregates, which are a potential aging factor in old-pole cell lineages, and found that these aggregates exhibited a tendency to preferentially remain at the old poles for several generations. However, the aggregates were eventually segregated from old-pole cells upon cell division and probabilistically allocated to new-pole cells. We found that cell deaths were typically preceded by sudden acceleration of protein aggregation; thus, a relatively large amount of protein aggregates existed at the very ends of the dead cell lineages. Our lineage tracking analyses, however, revealed that the quantity and inheritance of protein aggregates increased neither cellular generation time nor cell death initiation rates. Furthermore, our results demonstrated that unusually large amounts of protein aggregates induced by oxidative stress exposure did not result in aging; old-pole cells resumed normal growth upon stress removal, despite the fact that most of them inherited significant quantities of aggregates. These results collectively indicate that protein aggregates are not a major determinant of triggering cell death in S. pombe and thus cannot be an appropriate molecular marker or index for replicative aging under both favorable and stressful environmental conditions.

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Section: Resultsmentioning

confidence: 99%

Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe

Nakaoka

Wakamoto

2017

PLoS Biol

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“…In any event, the loss of both hsp104 and hsp78 genes in metazoans (Erives and Fassler, 2015 ) is striking, and opens the debate whether or not one or more genes can have the functions of these chaperones in animals (Mokry et al, 2015 ; Wortmann et al, 2015 ). Erives and Fassler ( 2015 ) showed that the ANKCLP gene occurs alongside the Hsp104 and Hsp78 genes in choanoflagellates, indicating that it may be a fusion of an N-terminal ankyrin domain and the C-terminal domain of a clp gene.…”

Section: Hsp78mentioning

confidence: 99%

“…The AAA family is very large, including several clp members that are involved in remodeling target proteins (Hanson and Whiteheart, 2005 ). Among the members of the clp proteins within the AAA family are ClpB and Hsp104, well known chaperones which have disaggregase activities that can solubilize aggregates (for reviews see Shorter, 2008 ; Zolkiewski et al, 2012 ; Mokry et al, 2015 ). These aggregates are soluble or insoluble non-physiologically associations of misfolded proteins via exposed hydrophobic regions that are strongly correlated with diseases (for reviews see Ramos and Ferreira, 2005 ; Chiti and Dobson, 2006 ; Doyle et al, 2013 ; Knowles et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Hsp78 (78 kDa Heat Shock Protein), a Representative AAA Family Member Found in the Mitochondrial Matrix of Saccharomyces cerevisiae

Abrahão

Mokry

Ramos

2017

Front. Mol. Biosci.

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ATPases associated with diverse cellular activities (AAA+) form a superfamily of proteins involved in a variety of functions and are characterized by the presence of an ATPase module containing two conserved motifs known as Walker A and Walker B. ClpB and Hsp104, chaperones that have disaggregase activities, are members of a subset of this superfamily, known as the AAA family, and are characterized by the presence of a second highly conserved motif, known as the second region of homology (SRH). Hsp104 and its homolog Hsp78 (78 kDa heat shock protein) are representatives of the Clp family in yeast. The structure and function of Hsp78 is reviewed and the possible existence of other homologs in metazoans is discussed.

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“…13,14 A moderate level of Hsp104 is required for [PSI C ] prion propagation as overproduction or deletion of Hsp104 cures the [PSI C ] prion in yeast. 15,16 Since, Hsp104 disaggregates the misfolded protein after heat shock, it is postulated that Hsp104 generates "propagons" by fragmenting the prion polymers that are available for further polymerization and therefore maintain the prion propagation. 7 Another model proposes that elevated levels of Hsp104 cure [PSI C ] prion by dissolution of the prion seeds, the evidence for this model came from the observation of the diffuse expression of Sup35 tagged with GFP when Hsp104 was overexpressed in [PSI C ] cells, 17 and a large fraction of soluble Sup35 was observed in the cell lysate of [PSI C ] with excess of Hsp104 expression.…”

Section: Introductionmentioning

confidence: 99%

The small heat shock protein Hsp31 cooperates with Hsp104 to modulate Sup35 prion aggregation

Aslam

Tsai

Hazbun

2016

Prion

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The yeast homolog of DJ-1, Hsp31, is a multifunctional protein that is involved in several cellular pathways including detoxification of the toxic metabolite methylglyoxal and as a protein deglycase. Prior studies ascribed Hsp31 as a molecular chaperone that can inhibit α-Syn aggregation in vitro and alleviate its toxicity in vivo. It was also shown that Hsp31 inhibits Sup35 aggregate formation in yeast, however, it is unknown if Hsp31 can modulate [PSI] phenotype and Sup35 prionogenesis. Other small heat shock proteins, Hsp26 and Hsp42 are known to be a part of a synergistic proteostasis network that inhibits Sup35 prion formation and promotes its disaggregation. Here, we establish that Hsp31 inhibits Sup35 [PSI] prion formation in collaboration with a well-known disaggregase, Hsp104. Hsp31 transiently prevents prion induction but does not suppress induction upon prolonged expression of Sup35 indicating that Hsp31 can be overcome by larger aggregates. In addition, elevated levels of Hsp31 do not cure [PSI] strains indicating that Hsp31 cannot intervene in a pre-existing prion oligomerization cycle. However, Hsp31 can modulate prion status in cooperation with Hsp104 because it inhibits Sup35 aggregate formation and potentiates [PSI] prion curing upon overexpression of Hsp104. The absence of Hsp31 reduces [PSI] prion curing by Hsp104 without influencing its ability to rescue cellular thermotolerance. Hsp31 did not synergize with Hsp42 to modulate the [PSI] phenotype suggesting that both proteins act on similar stages of the prion cycle. We also showed that Hsp31 physically interacts with Hsp104 and together they prevent Sup35 prion toxicity to greater extent than if they were expressed individually. These results elucidate a mechanism for Hsp31 on prion modulation that suggest it acts at a distinct step early in the Sup35 aggregation process that is different from Hsp104. This is the first demonstration of the modulation of [PSI] status by the chaperone action of Hsp31. The delineation of Hsp31's role in the chaperone cycle has implications for understanding the role of the DJ-1 superfamily in controlling misfolded proteins in neurodegenerative disease and cancer.

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Disaggregases, molecular chaperones that resolubilize protein aggregates

Cited by 25 publications

References 162 publications

Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe

Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe

Hsp78 (78 kDa Heat Shock Protein), a Representative AAA Family Member Found in the Mitochondrial Matrix of Saccharomyces cerevisiae

The small heat shock protein Hsp31 cooperates with Hsp104 to modulate Sup35 prion aggregation

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