Abstract
The yeast prion [SWI+], formed of heritable amyloid aggregates of the Swi1 protein, results in a partial loss of function of the SWI/SNF chromatin-remodeling complex, required for the regulation of a diverse set of genes. Our genetic analysis revealed that [SWI+] propagation is highly dependent upon the action of members of the Hsp70 molecular chaperone system, specifically the Hsp70 Ssa, two of its J-protein co-chaperones, Sis1 and Ydj1, and the nucleotide exchange factors of the Hsp110 family (Sse1/2). Notably, while all yeast prions tested thus far require Sis1, [SWI+] is the only one known to require the activity of Ydj1, the most abundant J-protein in yeast. The C-terminal region of Ydj1, which contains the client protein interaction domain, is required for [SWI+] propagation. However, Ydj1 is not unique in this regard, as another, closely related J-protein, Apj1, can substitute for it when expressed at a level approaching that of Ydj1. While dependent upon Ydj1 and Sis1 for propagation, [SWI+] is also highly sensitive to overexpression of both J-proteins. However, this increased prion-loss requires only the highly conserved 70 amino acid J-domain, which serves to stimulate the ATPase activity of Hsp70 and thus to stabilize its interaction with client protein. Overexpression of the J-domain from Sis1, Ydj1, or Apj1 is sufficient to destabilize [SWI+]. In addition, [SWI+] is lost upon overexpression of Sse nucleotide exchange factors, which act to destabilize Hsp70's interaction with client proteins. Given the plethora of genes affected by the activity of the SWI/SNF chromatin-remodeling complex, it is possible that this sensitivity of [SWI+] to the activity of Hsp70 chaperone machinery may serve a regulatory role, keeping this prion in an easily-lost, meta-stable state. Such sensitivity may provide a means to reach an optimal balance of phenotypic diversity within a cell population to better adapt to stressful environments.
Highlights
Yeast prions are non-Mendelian genetic elements, most of which are amyloid aggregates formed by single proteins [1,2,3,4,5,6,7,8]
The presence of an amyloid prion is often associated with phenotypes that arise from the partial loss of function of the prionforming protein due to its sequestration in the aggregates
Relative to other prions, [SWI+] propagation is highly sensitive to perturbations in the activity of the Hsp70 machinery
Summary
Yeast prions are non-Mendelian genetic elements, most of which are amyloid aggregates formed by single proteins [1,2,3,4,5,6,7,8]. Physical transmission of these aggregates/seeds to daughter cells is required for propagation of the prion in the cell population [8,27,28,29] It has been known for some time that the action of the molecular chaperone Hsp104, Author Summary. We found that, compared to previously wellstudied prions, [SWI+] is highly sensitive to changes in the activities of molecular chaperones, components of the Hsp machinery. Both under- and overexpression of components of this system initiated rapid loss of the prion from the cell population. The idea that stress conditions may affect the stability of [SWI+] in cell populations due to this sensitivity to chaperone activity is addressed
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