Amyloid-based yeast prions identified to date.
Yeast prions are self-templating amyloid aggregates composed of misfolded cellular proteins. In order to propagate, yeast prions must be broken into heritable seeds that are passed to subsequent generations. The replication step of the prion propagation cycle is accomplished by the actions of molecular chaperones, which bind to and serve the fibers through a process called disaggregation. Prions can be thought of as molecular diseases that have hijacked the chaperones for their continued existence. When viewed in this way, the study of yeast prions has been very informative about the interactions among of the molecular chaperones. This chapter focuses on the role of a single Hsp40 or J-protein, Sis1, in the propagation of yeast prions. While Sis1 seems to be required for the maintenance of many different prions, various prions depend on Sis1 in different ways, perhaps due to differences in underlying amyloid structure. New evidence is emerging that Sis1 is important for processes that may not involve prion replication activity, providing an intriguing alternative explanation for the observed differences in the prions’ reliance on Sis1.
- yeast prion
- prion propagation
In 1994, Reed Wickner solved a puzzle that had beguiled
||Sup35||Nonsense suppression||Weak and strong variants|||
|[URE3]||Ure2||Derepression of nitrogen utilization pathways|||
||Rnq1||Rnq1 aggregation; decrease in de novo [
||Also known as [
||Sfp1||Antisuppression (reverse of [
||Not dependent on Hsp104|||
||Swi1||Poor growth on alternative carbon sources|||
||Mot3||Pseudohyphal growth and biofilm formation|||
||Mod5||Fluconazole resistance||Prion-forming domain isnot Q/N rich|||
The molecular chaperones were first identified in
|Class||Structure and function||Yeast||
|Hsp100||Hexameric AAA+ ATPase disaggregase||Hsp104||ClpB|
|Hsp90||Dimeric posttranslational modifier of client activity||Hsc82, Hsp82||HtpG|
|Hsp70||Holdase; binds and releases unfolded polypeptides||Ssa1 through Ssa4; Ssb1, Ssb2||DnaK|
|Hsp60||Tetradecameric mitochondrial chaperonin||Hsp60||GroEL|
|Hsp40||Also called J-protein; dimeric stimulator ofHsp70 ATPase; substrate specificity||Sis1, Ydj1, Jjj1; 23 others (reviewed in Ref. )||DnaJ, CbpA, DjlA|
|Small HSPs||Crystallins, promoters of aggregation||Hsp42, Hsp26|
The first findings that molecular chaperones played a role in yeast prions were the discovery that overexpression of the AAA+ ATPase disaggregase Hsp104 “cured” cells of the [
This chapter focuses on the role of the Hsp40 Sis1 in yeast prion biology. Figure 1 shows a cartoon of Sis1 domain structure. In addition to playing a central role in yeast prion propagation, Sis1 is essential for cell viability . While the exact nature of Sis1’s essential function remains unknown, it is clear that its regulation of Hsp70 function (via stimulation of Hsp70 ATPase, reviewed in Ref. ) is important, since the minimal Sis1 fragment required for growth is the Hsp70-interacting J-domain and the adjacent glycine/phenylalanine region . Likewise, a single point mutation in any of the three universally conserved residues of the HPD (histidine, proline and aspartate) motif abolishes stimulation of Hsp70 ATPase in vitro  and is lethal in vivo . Whether the essential function of Sis1 is also required for prion propagation is unclear, as will be discussed. The nonessential functions of Sis1 can easily be studied using yeast prions, because the different yeast prions all seem to have differing requirements of Sis1 [30–33]. It is these nonessential Sis1 functions that are the focus of this chapter.
2. Yeast prion biology
Most yeast prions share a similar in-register parallel beta-sheet amyloid core composed of a prion-forming domain that is rich in asparagine and glutamine residues [35–37]. In the prion minus state, these domains are mostly unstructured and the protein is soluble and active. In the prion plus state, the prion-forming domains of newly synthesized prion protein molecules are recruited to the ends of an amyloid fiber. The in-register character of the beta-sheet core serves as a template for the incoming soluble molecule . In addition to the different prions shown in
, some prions such as [
Most prion proteins also have globular domains that do not misfold to participate in the amyloid core [43, 44]. However, because the amyloid fiber as a whole is insoluble, these globular domains are essentially depleted from the cytosol. For two of the most studied prions, [
Ure2, the determinant of the [URE3] prion, is a regulator of yeast nitrogen catabolism [47, 48]. In the presence of certain nitrogen sources, soluble Ure2 binds to and sequesters transcription factors such as Gln3 in the cytoplasm . When Ure2 is depleted, the transcription factors are free to move into the nucleus, where they activate genes such as
Spontaneous breakage of amyloid fibers, even thermodynamically unstable ones, does not occur often enough to maintain the prion phenotype in an expanding yeast population. This inefficient breakage is evident in the reliance of all amyloid-based yeast prions, except one (see
) , on the activity of the Hsp104 molecular disaggregase. The absence of the
3. Generalized role of Sis1 in prion propagation
The first report that the essential yeast J-protein Sis1 was involved in prion propagation was in 2001 by a collaborative effort between Elizabeth Craig and Susan Lindquist . Following up on earlier reports and communications that Sis1 co-immunoprecipitated with Rnq1 , the determinant of the [
A major step toward answering these questions came from the Craig lab in 2007 . Aron and colleagues introduced into their strains a tetracycline-repressible system that shuts off transcription of target genes, which they called “TET-Off” , in this case
Having established that the [
In 2008 Jonathan Weissman’s laboratory answered one of the most important remaining questions: What does Sis1 do in prion propagation ? By creating chimeric domain-swapped constructs between Hsp104 and the
The investigations into the collaborative barrier that exists between prokaryotic and eukaryotic Hsp100s and Hsp70s ended up reinforcing the notion that Sis1 provides the disaggregation machinery’s specificity for amyloid substrates. In 2010 and 2011, two studies revealed the underlying reason of why ClpB cannot function in yeast and Hsp104 cannot function in
In a follow-up to the Miot study, the Masison lab extended these findings to the prions [
4. Specialized roles of Sis1 in propagation of the different prions
Amyloid fiber breakage is a process that is fundamental for the propagation of yeast prions. Left alone, intracellular amyloid fibers would be a fleeting phenomenon. This failure to propagate is due simply to the fact that without breakage, upon mitosis there are two cells but only one amyloid fiber. While it is easy to imagine an unstable amyloid fiber able to generate enough seeds for propagation spontaneously, prions that do not require Hsp104 have been rarely observed  and this does not necessarily mean that propagation occurs by spontaneous breakage. Rather, amyloid-based yeast prions require molecular chaperones and specifically they require Sis1, as we have seen. At the same time, not all amyloids are the same in terms of their thermodynamic and structural properties . It makes sense that a thermodynamically sturdy amyloid fiber would need an increased capability to resolve complex structures compared to an amyloid composed of the same protein but in less stable conformation. The emerging view is that Sis1 plays a major role in meeting the different demands imposed by various amyloids. The discovery and characterization of distinct prion variants have proven to be a valuable tool in shaping the field’s understanding of the redundancy and variability of chaperone functions .
As noted previously, Higurashi showed that while the three most-studied prions, strong [
Higurashi showed that [URE3] was lost much more rapidly than strong [
When Reidy and colleagues investigated whether their Sis1-Ydj1 chimeras could propagate [URE3], they discovered that in addition to the C-terminal domain of Sis1, the glycine-rich domain (consisting of both the G/F region and the glycine/methionine (G/M) region) was also required. They then employed the suite of Sis1 domain truncations used in the Yan, Kirkland and Harris papers to determine the specific requirements for Sis1 on [URE3] propagation, information that was lacking. Remarkably, [URE3] was lost or greatly destabilized by any of the mutations in Sis1 that were tested . In some cases, the prion could be selected for and maintained in the presence of a particular Sis1 truncation, such as deletion of the dimerization motif, by growth on media-lacking adenine. However, the prion was rapidly lost upon relief of the selection pressure. Such observations are noteworthy but do not necessarily constitute ability to efficiently support prion propagation. Thus, [URE3] exhibited the highest dependence on Sis1 function, confirming the initial finding by Higurashi.
Interestingly, in the 2008 Higurashi paper, the authors proposed that the strong reliance on Sis1 by [URE3] they observed may explain a phenomenon first reported in 2000 by Reed Wickner’s group . Moriyama and colleagues reported that in addition to requiring Hsp104 for propagation, the [URE3] prion was cured by overexpression of the Hsp40 Ydj1. [URE3] was unique among the yeast prions in being able to be cured by overexpression of Ydj1. Higurashi showed that a mutated Ydj1 that could no longer interact with Hsp70 failed to cure [URE3] when overexpressed and also showed that overexpression of just the J-domain of Ydj1 or a different J-protein called Jjj1 could cure [URE3] when overexpressed . Higurashi concluded that the curing first observed by Moriyama was not due to Ydj1 itself, but rather the result of having too many J-domains in the cell that perhaps interfered with prion propagation through unproductive interactions with Hsp70. This theory was strengthened by a study published by the Masison group in early 2009 . Sharma and colleagues determined that Ydj1 curing of [URE3] was mediated through Hsp70 by screening for random mutations in Ydj1 that failed to cure [URE3] when overexpressed. Similar to the finding in the Higurashi study that the J-domain of Jjj1 could also cure [URE3], Sharma reported that overexpression of the J-domain of Sis1 also resulted in [URE3] destabilization. Thus, the two studies complemented each other and supported the idea that overabundant J-domains destabilize [URE3], mediated somehow through Hsp70. These studies conflicted with a study published in 2006 . Working with purified components, Lian and colleagues reported that Ydj1 interfered with the ability of Ure2 to form amyloid in vitro in a concentration-dependent manner. The authors extended these results to conclude that overexpressed Ydj1 cured [URE3] prions in vivo through direct inhibition of the Ure2 amyloid growth. However, the effect of Ydj1 on Ure2 amyloid formation was mostly limited to increasing the lag time of amyloid formation along with a decrease in overall yield. When Ydj1 was added to Ure2 amyloid reactions during logarithmic growth of amyloid fibers, conditions that arguably more closely resembled the in vivo situation of overexpressing Ydj1 in a cell that contains actively growing amyloid, no effect on Ure2 amyloid formation kinetics was observed.
The Higurashi model of Ydj1-mediated curing of [URE3] was strengthened by findings in Sis1-Ydj1 chimera paper that further characterized [URE3]’s strong dependence on Sis1 . When the chimeras that could not propagate [URE3] in place of normal Sis1 (those that did not have both the glycine-rich and C-terminal domains of Sis1) were overexpressed in wild-type cells, rapid loss of [URE3] was observed . Removing the dimerization motif from the chimeras that contained the C-terminal domain of Sis1 resulted in amelioration of curing, suggesting that the chimeras destabilized [URE3] by dimerizing with normal Sis1 monomers that were thus unable to propagate [URE3]. The authors then reasoned that [URE3] loss was due to defects in Sis1’s ability to propagate the prion and extended this idea to Ydj1-mediated curing. Perhaps, Ydj1 simply outcompeted Sis1 for interaction with the disaggregation machinery to such a level that was detrimental to [URE3]. Since [URE3] was much more sensitive to Sisi1 alteration than other prions, this may explain why overexpressed Ydj1 had no effect on them. The authors tested this hypothesis by co-overexpressing Sis1 at the same time as Ydj1. In line with their model, they observed that elevating Sis1 levels reduced Ydj1-mediated curing of [URE3] by tenfold, but had no effect on curing by expression of a dominant negative Hsp104 allele. Thus, the initial idea put forth by Higurashi regarding overexpressed Ydj1 curing of [URE3], that is, an imbalance of J-domains in the cell, was correct.
From these studies a correlation is evident that the demand on Sis1 increases with thermostability of the underlying amyloid. Based on the Kirkland, Harris and Reidy papers, one can rank the four prions by increasing dependence on Sis1 as strong [
5. The present and future of Sis1 research
Sis1 is a busy molecule, as we have seen. While the reliance on different functions of Sis1 is well documented, there remains a lack of understanding as to what these functions actually are. It is likely that these functions can be thought of as fine adjustments on the primary function of assisting Hsp70 in substrate delivery to Hsp104. However, this model does not satisfactorily explain why a minimal Sis1 molecule lacking the entire substrate-binding domain is able to propagate some prions such as strong [
One intriguing idea that has emerged is that Sis1 may be functioning in other pathways that are important for prion stability that are not well understood. In 2008 Reed Wickner’s lab reported that overexpression of Btn2 or its homolog, a previously uncharacterized open reading frame that the authors named Cur1, cured cells of [URE3] . Btn2 was shown previously to be involved with endosome trafficking . Kryndushkin and colleagues also observed that deletion of both
This research was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases. I thank my Laboratory of Biochemistry and Genetics colleagues for thoughtful discussions and critical reading of the manuscript.
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