Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
Cell. 2012 Dec 7;151(6):1308-18. 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.
在芽殖酵母中，Hsp70 伴侣蛋白 Ssa1-4 的基本功能通过表达水平、同工型特异性和共伴侣活性来调节。我们发现，Ssa1 T36 的磷酸化在一个在 Hsp70 蛋白中保守的细胞周期蛋白依赖性激酶 (CDK) 共识位点上，改变了共伴侣和客户的相互作用，这表明了一个新的调节范式。T36 磷酸化触发 Ydj1 的位移，使 Ssa1 能够与 G1 细胞周期蛋白 Cln3 结合并促进其降解。在氮饥饿或交配激素刺激下，应激 CDKs Pho85 会磷酸化 T36，使 Cln3 不稳定，从而延迟 S 期的开始。反过来，有丝分裂 CDK Cdk1 磷酸化 T36 以阻止 Cln3 在 G2/M 中的积累。从酵母到人类的广泛保守性表明，Hsc70 T38 的 CDK 依赖性磷酸化同样调节 Cyclin D1 的结合和稳定性。这些结果确立了 Hsp70 伴侣蛋白作为信号转导物的积极作用，介导了 G1 细胞周期蛋白丰度和活性的生长控制。
