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Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants

Significance The [PSI+] prion (infectious protein) is an amyloid (filamentous polymer) of the Sup35 protein, producing detrimental effects on yeast. We find that at their normal expression levels the core components of nonsense-mediated mRNA decay for mRNA quality control, Upf1p, Upf2p, and Upf3p, block the propagation of most new [PSI+] prion variants. The curing mechanism relies upon both Sup35p-binding by each Upf protein and by the trimeric Upf complex. Our results support the notion that normal protein–protein interactions prevent abnormal interactions. The yeast prion [PSI+] is a self-propagating amyloid of Sup35p with a folded in-register parallel β-sheet architecture. In a genetic screen for antiprion genes, using the yeast knockout collection, UPF1/NAM7 and UPF3, encoding nonsense-mediated mRNA decay (NMD) factors, were frequently detected. Almost all [PSI+] variants arising in the absence of Upf proteins were eliminated by restored normal levels of these proteins, and [PSI+] arises more frequently in upf mutants. Upf1p, complexed with Upf2p and Upf3p, is a multifunctional protein with helicase, ATP-binding, and RNA-binding activities promoting efficient translation termination and degradation of mRNAs with premature nonsense codons. We find that the curing ability of Upf proteins is uncorrelated with these previously reported functions but does depend on their interaction with Sup35p and formation of the Upf1p–Upf2p–Upf3p complex (i.e., the Upf complex). Indeed, Sup35p amyloid formation in vitro is inhibited by substoichiometric Upf1p. Inhibition of [PSI+] prion generation and propagation by Upf proteins may be due to the monomeric Upf proteins and the Upf complex competing with Sup35p amyloid fibers for available Sup35p monomers. Alternatively, the association of the Upf complex with amyloid filaments may block the addition of new monomers. Our results suggest that maintenance of normal protein–protein interactions prevents prion formation and can even reverse the process.