Dual role of ribosome-associated chaperones in prion formation and propagation

Chaperones of the diverse ubiquitous Hsp70 family are involved in the regulation of ordered self-perpetuating protein aggregates (amyloids and prions), implicated in both devastating diseases and protein-based inheritance. Yeast ribosome-associated chaperone complex (RAC), composed of the Hsp40 prot...

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Bibliographic Details
Published in:Current Genetics 2016-11, Vol.62 (4), p.677-685
Main Authors: Chernoff, Yury O., Kiktev, Denis A.
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Cell Biology
Life Sciences
Macromolecular Substances - metabolism
Microbial Genetics and Genomics
Microbiology
Molecular Chaperones - chemistry
Molecular Chaperones - metabolism
Plant Sciences
Prions - genetics
Prions - metabolism
Protein Aggregates
Protein Aggregation, Pathological - genetics
Protein Aggregation, Pathological - metabolism
Protein Binding
Protein Interaction Domains and Motifs
Proteomics
Review
Ribosomes - genetics
Ribosomes - metabolism
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Summary:Chaperones of the diverse ubiquitous Hsp70 family are involved in the regulation of ordered self-perpetuating protein aggregates (amyloids and prions), implicated in both devastating diseases and protein-based inheritance. Yeast ribosome-associated chaperone complex (RAC), composed of the Hsp40 protein Zuo1 and non-canonical Hsp70 protein Ssz1, mediates association of the Hsp70 chaperone Ssb with translating ribosomes. Ssb participates in co-translational protein folding, regulation of premature translation termination, and ribosome biogenesis. The loss of Ssb or disruption of RAC results in the increased formation of [ PSI + ], a prion form of the translation termination factor Sup35 (eRF3). This implicates co-translational protein misfolding in de novo prion formation. However, RAC disruption also destabilizes pre-existing [ PSI + ] prions, as Ssb, released from ribosomes to the cytosol in the absence of RAC, antagonizes the function of the major cytosolic chaperone, Ssa, in prion propagation. The mechanism of the Ssa/Ssb antagonism is currently under investigation and may include a competition for substrates and/or co-chaperones. Notably, yeast cells with wild-type RAC also release Ssb to the cytosol in certain unfavorable growth conditions, and Ssb contributes to increased prion loss in these conditions. This indicates that the circulation of Ssb between the ribosome and cytosol may serve as a physiological regulator of the formation and propagation of self-perpetuating protein aggregates. Indeed, RAC and Ssb modulate toxicity of some aggregating proteins in yeast. Mammalian cells lack the Ssb ortholog but contain a RAC counterpart, apparently recruiting other Hsp70 protein(s). Thus, amyloid modulation by ribosome-associated chaperones could be applicable beyond yeast.
ISSN:0172-8083
1432-0983
DOI:10.1007/s00294-016-0586-2