Small Heat Shock Proteins Potentiate Amyloid Dissolution by Protein Disaggregases from Yeast and Humans

Duennwald, Martin L.; Echeverria, AnaLisa; Shorter, James

doi:10.1371/journal.pbio.1001346

Cited by 171 publications

(181 citation statements)

References 95 publications

(204 reference statements)

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…It is possible that Btn2p and Cur1p participate in completely different systems, but their sequence similarity suggests that they may be alternative components of the same antiprion apparatus. (25), and is reported to cure [PSI+] when overproduced (24). We found that overexpression of Hsp42 cures [URE3 -1] and that this curing is essentially eliminated in a btn2Δ cur1Δ strain (Fig.…”

Section: Mutation and Segregation Of [Ure3-bcs]mentioning

confidence: 56%

See 1 more Smart Citation

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

[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...

show abstract

Section: Mutation and Segregation Of [Ure3-bcs]mentioning

confidence: 56%

“…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%

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

“…[78][79][80] Thus, amyloid fibrils and toxic oligomers are not intractable and can be eliminated rapidly by Hsp104. 61,73,[77][78][79][80][81][82][83][84]87,91 Inexplicably, Hsp104 has no metazoan ortholog despite being highly conserved in bacteria, plants, fungi, chromista, and protozoa. 39,40,52 The reason for the loss of Hsp104 from metazoan lineages is uncertain, especially as Hsp104 can be expressed safely and broadly in worm, fly, mouse, and rat.…”

Section: Applying Hsp104 and Engineered Variants To Deleterious Protementioning

confidence: 99%

Engineering enhanced protein disaggregases for neurodegenerative disease

Jackrel

Shorter

2015

Prion

Self Cite

103

View full text Add to dashboard Cite

ABSTRACT. Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious a-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.

show abstract

“…rapid disaggregase activity, disassembling proteins from aggregated conformations in collaboration with Hsp110, Hsp70, and Hsp40. 16,17,20,21 Using proteins in the Hsp100 family to reverse human disease phenotypes is intriguing, because the ability of Hsp100 proteins to rapidly untangle proteins from pre-existing inclusions would seem to have far greater therapeutic value than solely preventing aggregation. 20,22 While Hsp100 proteins are highly conserved in eubacteria and the vast majority of eukaryotes, Hsp104 from the budding yeast Saccharomyces cerevisiae is of particular interest, because it is the only protein known to rapidly disassemble amyloid and toxic preamyloid oligomers, but has no metazoan homolog.…”

mentioning

confidence: 99%

Reversing deleterious protein aggregation with re-engineered protein disaggregases

Jackrel

Shorter

2014

Cell Cycle

Self Cite

View full text Add to dashboard Cite

Small Heat Shock Proteins Potentiate Amyloid Dissolution by Protein Disaggregases from Yeast and Humans

Abstract: The authors define how small heat-shock proteins synergize to regulate the assembly and disassembly of a beneficial prion, and then they exploit this knowledge to identify the human amyloid depolymerase.

Cited by 171 publications

References 95 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

Engineering enhanced protein disaggregases for neurodegenerative disease

Reversing deleterious protein aggregation with re-engineered protein disaggregases

Contact Info

Product

Resources

About