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.
Yeast prions are heritable genetic elements, formed spontaneously by aggregation of a single protein. Prions can thus generate diverse phenotypes in a dominant, non-Mendelian fashion, without a corresponding change in chromosomal gene structure. Since the phenotypes caused by the presence of a prion are thought to affect the ability of cells to survive under different environmental conditions, those that have global effects on cell physiology are of particular interest. Here we report the results of a study of one such prion, [ SWI +], formed by a component of the SWI/SNF chromatin-remodeling complex, which is required for the regulation of a diverse set of genes. We found that, compared to previously well-studied prions, [ SWI +] is highly sensitive to changes in the activities of molecular chaperones, particularly components of the Hsp70 machinery. Both under- and over-expression of components of this system initiated rapid loss of the prion from the cell population. Since expression of molecular chaperones, often known as heat shock proteins, are known to vary under diverse environmental conditions, such “chaperone sensitivity” may allow alteration of traits that under particular environmental conditions convey a selective advantage and may be a common characteristic of prions formed from proteins involved in global gene regulation.