The Yeast Prion [SWI+] Abolishes Multicellular Growth by Triggering Conformational Changes of Multiple Regulators Required for Flocculin Gene Expression

Abstract

Summary While transcription factors are prevalent among yeast prion proteins, the role of prion-mediated transcriptional regulation remains elusive. We show here that the yeast prion [SWI+] abolishes flocculin (FLO) gene expression and results in a complete loss of multicellularity. Further investigation demonstrates that besides Swi1, multiple other proteins essential for FLO expression, including Mss11, Sap30, and Msn1 also undergo conformational changes, and become inactivated in [SWI+] cells. Moreover, the asparagine-rich region of Mss11 can exist as prion-like aggregates specifically in [SWI+] cells, which are SDS-resistant, heritable, and curable, but become metastable after separation from [SWI+]. Our findings thus reveal a prion-mediated mechanism through which multiple regulators in a biological pathway can be inactivated. In combination with the partial loss-of-function phenotypes of [SWI+] cells on non-glucose sugar utilization, our data therefore demonstrate that a prion can influence differently on distinct traits through multi-level regulations, providing insights into the biological roles of prions.

Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

“…The beneficial phenotypes conferred by yeast prions are often observed under stress conditions, which has led to the suggestion that yeast prions constitute bet-hedging devices, which can reveal potentially adaptive genetic diversity in fluctuating environments (Du et al, 2015; Garcia and Jarosz, 2014; Halfmann et al, 2010; Halfmann and Lindquist, 2010; Masel and Bergman, 2003; Newby and Lindquist, 2013; Tyedmers et al, 2008). This process is facilitated by the conformational range of PrDs, which can access multiple, distinct cross-β structures or strains (Shorter, 2010).…”

Analysis of [SWI+] formation and propagation events

“…Although published data showed that these UASs within the FLO11 promoter could respond independently to diverse external and internal signals, determination of the SWI/SNF‐acting UASs was reported to be difficult (Rupp et al ., ; Braus et al ., ; Basu et al ., ). Since Swi1 is required to activate FLO11 gene expression (Basu et al ., ; Du et al ., ), we assumed that the SWI/SNF (thus, Swi1)‐acting sites are within the previously identified UASs but not URSs. To identify Swi1‐acting sites, we generated six truncated FLO11 upstream regulatory region containing various numbers of UASs (+) and/or URSs (‐) by PCR (Fig.…”

“…S3). As we showed previously (Du et al ., ), Chr::P FLO1 ‐URA3 can clearly distinguish [ SWI + ] and [ swi ‐ ] cells in both ‐uracil and +5‐FOA assays (Supporting Information Fig. S3) and thus it is, applicable as a useful [ SWI + ] reporter.…”

“…In the budding yeast Saccharomyces cerevisiae, at least nine prion proteins have been identified and additional potential prions may exist (Crow and Li, 2011;Suzuki et al, 2012;Halfmann et al, 2012;Chakrabortee et al, 2016). When these prion proteins adopt prion conformation(s), the resulting prions usually manifest as dominant and heritable features, mostly through modulation of important cellular processes such as transcription and translation (Serio and Lindquist, 1999;Alberti et al, 2009;Stein and True, 2014;Du et al, 2015). In addition, it has been shown that some yeast prions can exist in wild strains and their prion conformational switches can be environmentally responsive, suggesting a possible role of prionogenesis in yeast adaptation to environmental fluctuations (Tyedmers et al, 2008;Suzuki et al, 2012;Holmes et al, 2013;Jarosz et al, 2014).…”

Interaction of Prions Causes Heritable Traits in Saccharomyces cerevisiae

“…Prion formation leads to DNA-independent changes in heritable traits in microorganisms such as Saccharomyces cerevisiae and Podospora anserina [2,3]. For example, [ PSI + ] and [ ISP + ] prions, whose structural proteins are Sup35 and Sfp1, respectively, modulate nonsense suppression [2,4]; Swi1 in its prion state, [ SWI + ], causes a partial loss of function in utilizing non-glucose sugars and completely abolish yeast multicellularity [5,6], while Ure2 in its [ URE3 ] form changes nitrogen catabolism [2]. The HET-s protein of P .…”