Abstract #63

A prion-like phenotype conveys glucosamine resistance in S. cerevisiae. Jessica C. Brown, Susan Lindquist. MIT Biology/Whitehead Institute, MA.
   Several well-characterized fungal proteins can act as prions: proteins capable of multiple self-propagating conformations, each with different activities. Prion conformers allow a single genotype to exhibit multiple phenotypes with non-Mendelian inheritance. The best characterized phenotypes are [PSI+], the prion form of the translation termination factor Sup35p, and [URE3], the prion form of the nitrogen catabolite repressor Ure2p. Both are studied in S. cerevisiae but are conserved to such diverse fungi as C. albicans.
   S. cerevisiae displays a non-Mendelian inheritance pattern conveying resistance to the non-hydrolyzable glucose analog D-(+)-glucosamine ([GAR+]). [GAR+] mimics genetic characteristics of known yeast prions. [GAR+] appears spontaneously at a high frequency (~5 in 10^5 cells) and segregates in a non-Mendelian 4 [GAR+] to 0 [gar-] pattern following meiosis. [GAR+] can be inherited by cytoplasmic transfer without nuclear exchange and [GAR+] can be "cured" to [gar-] by altering levels of molecular chaperones. However, unlike the well-characterized [PSI+] and [URE3] prions, [GAR+] is not cured by change in Hsp104p levels. Instead, yeast strains deleted for Hsp70s ssa1/2 cannot propagate[GAR+].
   The causal agent underlying [GAR+] is unknown. However, [GAR+] shows pleiotropic biological properties, including altered cell wall composition and greater agar adhesion compared to [gar-]. [GAR+] cells also outcompete [gar-] cells when grown in a mixture of glucose and other carbon sources. Microarray analysis showed remarkably little difference in gene expression between [gar-] and [GAR+] with one exception: Hexose Transporter 3 is downregulated ~35 fold in [GAR+] compared to [gar-]. This localizes the GAR agent downstream of the glucose sensors Rgt2p and Snf3p. Overexpression of particular members of this pathway induce the [GAR+] and overexpression of others inhibit this induction, implying that [GAR+] appearance is regulated.

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