CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression

• Published in: Cell 2012-12, Vol.151 (6), p.1308-1318
• Main Authors: Truman, Andrew W., Kristjansdottir, Kolbrun, Wolfgeher, Donald, Hasin, Naushaba, Polier, Sigrun, Zhang, Hong, Perrett, Sarah, Prodromou, Chrisostomos, Jones, Gary W., Kron, Stephen J.
• Format: Article
• Language: English
• Subjects: Abundance; Adenosine Triphosphatases - metabolism; Cell Cycle; Cell Proliferation; Chaperones; Conservation; cyclin D1; Cyclin D1 - metabolism; Cyclin-dependent kinase; cyclins; Cyclins - metabolism; HEK293 Cells; HSC70 Heat-Shock Proteins - metabolism; Hsc70 protein; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; interphase; Nitrogen; Pheromones; Phosphorylation; S phase; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; signal transduction; Starvation; Stress; yeasts
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.10.051

In budding yeast, the essential functions of Hsp70 chaperones Ssa1–4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we find that phosphorylation of Ssa1 T36 within a cyclin-dependent kinase (CDK) consensus site conserved among Hsp70 proteins alters cochaperone and client interactions. T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation. The stress CDK Pho85 phosphorylates T36 upon nitrogen starvation or pheromone stimulation, destabilizing Cln3 to delay onset of S phase. In turn, the mitotic CDK Cdk1 phosphorylates T36 to block Cln3 accumulation in G2/M. Suggesting broad conservation from yeast to human, CDK-dependent phosphorylation of Hsc70 T38 similarly regulates Cyclin D1 binding and stability. These results establish an active role for Hsp70 chaperones as signal transducers mediating growth control of G1 cyclin abundance and activity. [Display omitted] ► First demonstration of regulation of Hsp70 function through CDK phosphorylation ► Cdk1 and Pho85 phosphorylate Ssa1 to regulate binding to Cln3 and Cln3 destruction ► Cln3 degradation requires both Cln3 phosphorylation and Cln3 binding to Ssa1 ► CDK-mediated phosphorylation of Hsc70 targets Cyclin D1 abundance and activity Cyclin-dependent kinases directly phosphorylate yeast Hsp70 to enhance its interaction with Cyclin 3, triggering its destruction and the G1/S checkpoint, showing that chaperone proteins can act as signal transducers during cell-cycle progression.