Hsp42 is required for sequestration of protein aggregates into deposition sites in <i>Saccharomyces cerevisiae</i>

Specht, Sebastian; Miller, Stephanie B.M.; Mogk, Axel; Bukau, Bernd

doi:10.1083/jcb.201106037

Cited by 247 publications

(445 citation statements)

References 36 publications

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“…Thus, Btn2p (or associated proteins) recognizes the prion form of Ure2p as distinct from nonprion aggregates of the same protein. Only accumulation of aggregates at the peripheral site requires Hsp42p, and Hsp42p is found to localize at that site (23). We find that Hsp42 is needed for Btn2p overproduction curing, raising the possibility that Btn2p may bring prion aggregates to the peripheral site.…”

Section: Discussionmentioning

confidence: 72%

“…Specht et al found that although benomyl inhibited formation of both peripheral and juxtanuclear aggregate foci, a benomyl-resistant tubulin2 mutant showed the same effect. In contrast, LatrunculinA, which depolymerizes the actin cytoskeleton, inhibited accumulation of aggregates at both sites, but a mutation in actin-1 that prevents LatrunculinA action prevented this action of the drug (23). Thus, the actin cytoskeleton is invovled in IPOD and JUNQ focus formation, distinguishing both from the aggresome.…”

Section: Significancementioning

confidence: 94%

“…Specht et al (23) found that Hsp42 was necessary for aggregate accumulation at the peripheral site, but not at the juxtanuclear site. They found that Hsp42 did not affect the localization of "amyloidogenic" aggregates of Rnq1p, but again, the cells were not carrying the corresponding prion, [PIN+], so these aggregates were likely nonamyloid.…”

Section: Significancementioning

confidence: 99%

“…Thus, the actin cytoskeleton is invovled in IPOD and JUNQ focus formation, distinguishing both from the aggresome. Overproduction of either Hsp26 or Hsp42 were reported to cure the [PSI+] prion (24), but hsp26Δ did not affect IPOD or JUNQ aggregate focus formation (23). Hsp42p associates with Btn2p in vivo (25).…”

Section: Significancementioning

confidence: 99%

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Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

Wickner

Bezsonov

Bateman

2014

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

120

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[URE3] is an amyloid prion of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. Overproduction of Btn2p, involved in late endosome to Golgi protein transport, or its paralog Cur1p, cures [URE3]. Btn2p, in curing, is colocalized with Ure2p in a single locus, suggesting sequestration of Ure2p amyloid filaments. We find that most [URE3] variants generated in a btn2 cur1 double mutant are cured by restoring normal levels of Btn2p and Cur1p, with both proteins needed for efficient curing. (1-4). Ure2p normally functions as a soluble regulator of nitrogen catabolism (5, 6), and its conversion to the aggregated amyloid prion form produces inappropriate derepression of many genes of nitrogen catabolism, resulting in slightly slowed growth (7). Many [URE3] isolates have a severe toxic effect, producing extremely slowed growth (8). A single protein sequence can assume any of many different heritable/infectious forms with different biological properties and, one infers, different protein conformations. The parallel in-register β-sheet architecture of the [URE3] prion amyloid (9) can explain the templating properties of this prion (10) and the ability of the Ure2p amyloid to act as a gene with multiple alleles (4).[PSI+] is similarly an amyloid prion of Sup35p, a subunit of the translation termination factor [reviewed by Liebman and Chernoff (11)], and [PIN+] is a prion of Rnq1p, a protein of unknown function (12)(13)(14).Eukaryotic cells deal with protein aggregates in several ways, including resolubilization, degradation, sequestration, and combinations of these processes. Several organelles and systems have been recognized to play a role in these processes, including vacuoles (the yeast equivalent of the mammalian lysosomes), the ubiquitin-proteasome systems, the autophagy system, and the various chaperones.In mammalian cells the aggresome is a centrosomal structure to which aggregates are brought in a microtubule-dependent process (15). A yeast site near the spindle pole body (the yeast centrosome) collects huntingtin/polyQ aggregates in a process that depends on microtubule function, suggesting that this is the yeast aggresome (16). Bmh1p, a 14-3-3 protein, was found associated with huntingtin in yeast aggresomes, and bmh1Δ prevented aggresome accumulation of huntingtin (16).Btn2p and Cur1p were found to cure the [URE3] prion when overproduced (17). These proteins are paralogs, members of the Hook family, consistent with their similar effects, but Btn2 localized to a site next to the nucleus, whereas Cur1 was localized largely within the nucleus (17). During the curing process, those [URE3] cells having both Ure2p-GFP aggregates and Btn2-RFP dots show striking colocalization (17-19). Partial colocalization of Btn2-RFP with Sup35NM-GFP in a [PSI+] strain or with the huntingtin-like Q103-GFP were also observed (17), but overexpression of Btn2p or Cur1p did not cure [PSI+]. Doubly deleted btn2Δ cur1Δ strains show an elevated seed number of [URE3] and partial resistance to prion curing by dimethyl sul...

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Section: Discussionmentioning

confidence: 72%

Section: Significancementioning

confidence: 94%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

Wickner

Bezsonov

Bateman

2014

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

120

View full text Add to dashboard Cite

show abstract

“…Instead, it aggregates in two different subcellular compartments -in the insoluble protein deposit (IPOD), which is close to the vacuole, and the juxtanuclear quality control compartment (JUNQ). In either, aggregated proteins are either refolded by chaperones or degraded by the proteasome (Kaganovich et al, 2008;Specht et al, 2011). Moreover, a new intra-nuclear inclusion (INQ) has been described recently for the deposition of nuclear and cytosolic misfolded proteins (Miller et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Goff¹,

Chesnel²,

Delalande³

et al. 2016

Journal of Cell Science

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Quality control mechanisms promote aggregation and degradation of misfolded proteins. In budding yeast, the human von HippelLindau protein ( pVHL, officially known as VHL) is misfolded and forms aggregates. Here, we investigated the aggregation of three pVHL isoforms ( pVHL213, pVHL160, pVHL172) in fission yeast. The full-length pVHL213 isoform aggregates in highly dynamic small puncta and in large spherical inclusions, either close to the nucleus or to the cell ends. The large inclusions contain the yeast Hsp104 chaperone. Aggregate clearance is regulated by proteasomal degradation. The pVHL160 isoform forms dense foci and large irregularly shaped aggregates. In silico, prediction of pVHL aggregation propensity identified a key aggregation-promoting region within exon 2. Consistently, the pVHL172 isoform, which lacks exon 2, formed rare reduced inclusions. We studied the aggregation propensity of pVHL variants harbouring missense mutations found in kidney carcinomas. We show that the P86L mutation stimulated small aggregate formation, the P146A mutation increased large inclusion formation, whereas the I151S mutant destabilized pVHL. The prefoldin subunit Pac10 (the human homolog VBP-1 binds to pVHL) is required for pVHL stability. Reduction of soluble functional pVHL might be crucial in VHL-related diseases.

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Defective mitochondrial import as a challenge for cellular protein homeostasis

2023

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Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.

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Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae

Abstract: The budding yeast heat shock protein Hsp42 coaggregates with misfolded proteins and may link those aggregates to further sorting factors.

Cited by 247 publications

References 36 publications

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants

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

Defective mitochondrial import as a challenge for cellular protein homeostasis

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