Yeast Endosulfines Control Entry into Quiescence and Chronological Life Span by Inhibiting Protein Phosphatase 2A

SummaryThe 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 (PP2ACdc55). Inhibition of PP2ACdc55 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 PP2ACdc55 in TORC1-/PKA-mediated regulation of quiescence and chronological life span.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Rim15, the yeast ortholog of greatwall kinase, phosphorylates the endosulfine Igo1 ► Phosphorylated Igo1 directly inhibits the Cdc55-protein phosphatase 2A (PP2ACdc55) ► Phosphoproteome studies identify the transcription factor Gis1 as a PP2ACdc55 target ► The Rim15-Igo1-PP2ACdc55 branch controls quiescence and chronological life span