Reed B. Wickner

We characterized (and in some cases discovered) two dsRNA viruses (L-A and L-B) and two (+) ssRNA viruses (20S and 23S RNA) of the yeast Saccharomyces cerevisiae, including virus structure, replication, expression, and host interactions. L-A uses ribosomal frameshifting and depends on Mak3p, an N-acetyl-transferase modifying the major coat protein for particle assembly. L-A protein expression is negatively regulated by the Ski proteins, thus preventing lethality of the M dsRNA satellite RNA of L-A. We discovered that yeast have prions, [URE3] a prion of Ure2p and [PSI+] a prion of Sup35p. We showed that the amyloids that are the basis of these prions has a folded, parallel, in-register, beta-sheet architecture, and based on this explained how prions can template their conformation, and thus act as genes. We showed that these prions are diseases of yeast (lethal in some cases and highly toxic in most cases), and uncovered six host anti-prion systems that cure most prions as they are formed. We also found that the host partially blocks prion formation, and has functions that prevent the toxicity of the few prions that are formed in spite of all these defenses. We are currently exploring the mechanisms of action of anti-prion proteins.