Amyloid conformation-dependent disaggregation in a reconstituted yeast prion system

Nakagawa, Yoshiko; Shen, Howard C.-H.; Komi, Yusuke; Sugiyama, Shinju; Kurinomaru, Takaaki; Tomabechi, Yuri; Krayukhina, Elena; Okamoto, Kenji; Yokoyama, Takeshi; Shirouzu, Mikako; Uchiyama, Susumu; Inaba, Megumi; Niwa, Tatsuya; Sako, Yasushi; Taguchi, Hideki; Tanaka, Motomasa

doi:10.1038/s41589-021-00951-y

Cited by 21 publications

(14 citation statements)

References 66 publications

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“…More recent work by Son and Wickner has demonstrated that most [ PSI + ] variants (amyloid polymorphisms) that arise in the absence of RAC can be cured by normal levels of Zuo1 and Ssz1 22 . Indeed, the de novo formation of prions depends on the balance between amyloid seed nucleation and clearance, and chaperones such as the disaggregase Hsp104 and the Hsp70/40 pair Ssa1 and Sis1 play critical roles in yeast prion propagation 33,34 . Amyloid disaggregation by Hsp104 can lead to either fragmentation (which enables propagation) or dissolution, and the presence of the prion form of Rnq1 (termed [ PIN + ] or [ RNQ + ]) was shown to promote [ PSI + ] formation by titrating Hsp104 activity on Sup35 amyloid 33 .…”

Section: Discussionmentioning

confidence: 99%

The human ribosome‐associated complex suppresses prion formation in yeast

et al. 2023

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Many human diseases are associated with the misfolding of amyloidogenic proteins.Understanding the mechanisms cells employ to ensure the integrity of the proteome is therefore a crucial step in the development of potential therapeutic interventions. Yeast cells possess numerous prion-forming proteins capable of adopting amyloid conformations, possibly as an epigenetic mechanism to cope with changing environmental conditions. The ribosome-associated complex (RAC), which docks near the ribosomal polypeptide exit tunnel and recruits the Hsp70 Ssb to chaperone nascent chains, can moderate the acquisition of these amyloid conformations in yeast. Here we examine the ability of the human RAC chaperone proteins Mpp11 and Hsp70L1 to function in place of their yeast RAC orthologues Zuo1 and Ssz1 in yeast lacking endogenous RAC and investigate the extent to which the human orthologues can perform RAC chaperone activities in yeast. We found that the Mpp11/Hsp70L1 complex can partially correct the growth defect seen in RACdeficient yeast cells, although yeast/human hetero species complexes were variable in this ability. The proportion of cells in which the Sup35 protein undergoes spontaneous conversion to a [PSI + ] prion conformation, which is increased in the absence of RAC, was reduced by the presence of the human RAC complex. However, the toxicity in yeast from expression of a pathogenically expanded polyQ protein was unable to be countered by the human RAC chaperones. This yeast system can serve as a facile model for studying the extent to which the human RAC chaperones contribute to combating cotranslational misfolding of other mammalian diseaseassociated proteins.

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Section: Discussionmentioning

confidence: 99%

The human ribosome‐associated complex suppresses prion formation in yeast

et al. 2023

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“…Studies in yeast showed the maintenance and propagation of three prions associated with Rnq1, Ure2, and Sup35 are dependent on an Hsp40 family protein Sis1 (Aron et al, 2007; Higurashi et al, 2008; Lopez et al, 2003). Sis1 acts as a disaggregase in collaboration with Hsp104 and Hsp70 by helping in the fragmentation of the oligomers of these prions to generate propagating seeds (Nakagawa et al, 2022). Another Hsp40 family protein Ydj1 together with Hsp70 has been found to inhibit the formation of Ure2 prion state in yeast by delaying its aggregation to form amyloid fibrils (Lian et al, 2007; Sharma et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Mrj an Hsp40 family chaperone regulates the oligomerization of Orb2 and long-term memory

Desai

Singh

Deo

et al. 2022

Preprint

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Orb2 the Drosophila homolog of Cytoplasmic polyadenylation element binding protein (CPEB) forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation are dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2A's prion-like oligomerization forms long-term memory but fails to maintain it over time. Since, this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Amongst these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, the knockdown of Mrj in the mushroom body neurons results in a deficit in long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating polysomes.

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“…Fragmentation of the Sup35 prion relies on sequential action of chaperones Sis1, Ssa and Hsp104 [ 113 ]. It is known that overproduction of Hsp104 does not improve fragmentation of Sup35 [ 114 ].…”

Section: Sup35 Variant Prion Structuresmentioning

confidence: 99%

“…Sis1 chaperone dimer is likely to be present at one per ten protomers, and the Ssa chaperones at one per two protomers [ 27 , 112 ], but only half of Ssa molecules are shown. Though a recent in vitro study on Sup35 fibrils suggested a ratio of one Sis1 dimer to two Ssa, these data were not directly quantified [ 113 ]. Hsp104 hexamer and the ribosome outline are shown.…”

Section: Sup35 Variant Prion Structuresmentioning

confidence: 99%

Structural Bases of Prion Variation in Yeast

Kushnirov

Dergalev

Alieva

et al. 2022

IJMS

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Amyloids are protein aggregates with a specific filamentous structure that are related to a number of human diseases, and also to some important physiological processes in animals and other kingdoms of life. Amyloids in yeast can stably propagate as heritable units, prions. Yeast prions are of interest both on their own and as a model for amyloids and prions in general. In this review, we consider the structure of yeast prions and its variation, how such structures determine the balance of aggregated and soluble prion protein through interaction with chaperones and how the aggregated state affects the non-prion functions of these proteins.

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Amyloid conformation-dependent disaggregation in a reconstituted yeast prion system

Cited by 21 publications

References 66 publications

The human ribosome‐associated complex suppresses prion formation in yeast

The human ribosome‐associated complex suppresses prion formation in yeast

Mrj an Hsp40 family chaperone regulates the oligomerization of Orb2 and long-term memory

Structural Bases of Prion Variation in Yeast

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