The prion-like determinant [ISP+] manifests itself as an antisuppressor of certain sup35 mutations. To establish that [ISP+] is indeed a new yeast prion, it is necessary to identify the gene that codes for the protein whose prion form is [ISP+]. Analysis of the transformants obtained by transformation of an [ISP+] strain with an insertion gene library revealed three genes controlling the [ISP+] maintenance: UPF1, UPF2, and SFP1. SFP1 codes for a potentially prionogenic protein, which is enriched in Asn and Gln residues, and is thereby the most likely candidate for the [ISP+] structural gene. UPF1 and UPF2 code for components of nonsense-mediated mRNA decay. The [ISP+] elimination caused by UPF1 and UPF2 inactivation was reversible, and Upf1p and Upf2p were not functionally related to phosphatase Ppz1p, which influences the [ISP+] manifestation. Possible mechanisms sustaining the influence of UPF1 and UPF2 on [ISP+] maintenance are discussed.