The TORC1 and PKA protein kinases are central elements of signaling networks that regulate eukaryotic cell proliferation in response to growth factors and/or nutrients. In yeast, attenuation of signaling by these kinases following nitrogen and/or carbon limitation activates the protein kinase Rim15, which orchestrates the initiation of a reversible cellular quiescence program to ensure normal chronological life span. The molecular elements linking Rim15 to distal readouts including the expression of Msn2/4- and Gis1-dependent genes involve the endosulfines Igo1/2. Here, we show that Rim15, analogous to the greatwall kinase in Xenopus, phosphorylates endosulfines to directly inhibit the Cdc55-protein phosphatase 2A (PP2A(Cdc55)). Inhibition of PP2A(Cdc55) preserves Gis1 in a phosphorylated state and consequently promotes its recruitment to and activation of transcription from promoters of specific nutrient-regulated genes. These results close a gap in our perception of and delineate a role for PP2A(Cdc55) in TORC1-/PKA-mediated regulation of quiescence and chronological life span.

6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases. Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome. 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.