CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression.
CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression.
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DOI：
10.1016/j.cell.2012.10.051
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发表时间：
2012-12-07
期刊：
影响因子：
64.5
通讯作者：
Kron SJ
中科院分区：
文献类型：
--
作者：
Truman AW;Kristjansdottir K;Wolfgeher D;Hasin N;Polier S;Zhang H;Perrett S;Prodromou C;Jones GW;Kron SJ
在出芽酵母中，Hsp70伴侣Ssa1-4的基本功能是通过表达水平、异构体特异性和伴侣活性来调控的。研究人员发现，在Hsp70蛋白中保守的周期蛋白依赖性激酶（CDK）共识位点上，Ssa1 T36的磷酸化改变了合作伙伴和客户的相互作用，这表明了一种新的调控模式。T36磷酸化触发Ydj1的位移，使Ssa1结合G1周期蛋白Cln3并促进其降解。胁迫CDK Pho85在氮饥饿或信息素刺激下磷酸化T36，破坏Cln3的稳定，延迟S期的开始。反过来，有丝分裂的CDK Cdk1磷酸化T36以阻断Cln3在G2/M中的积累。cdk依赖性的Hsc70 T38磷酸化类似地调节Cyclin D1的结合和稳定性，表明从酵母到人类的广泛保守性。这些结果表明，Hsp70伴侣作为信号转导介导G1周期蛋白丰度和活性的生长控制。►Cdk1和Pho85磷酸化Ssa1以调节与Cln3的结合和Cln3的破坏►Cln3的降解需要Cln3的磷酸化和Cln3与Ssa1的结合►CDK介导的Hsc70磷酸化目标是Cyclin D1的丰度和活性，周期蛋白依赖激酶直接磷酸化酵母Hsp70以增强其与Cyclin 3的相互作用，触发其破坏和G1/S检查点。表明伴侣蛋白在细胞周期进程中可以作为信号转导。
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. ► 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.
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影响因子：
12.3
作者：
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