Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.
Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.
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DOI：
10.1111/mmi.12960
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发表时间：
2015-05
影响因子：
3.6
通讯作者：
Chernoff YO
中科院分区：
文献类型：
--
作者：
Kiktev DA;Melomed MM;Lu CD;Newnam GP;Chernoff YO
交叉β纤维蛋白聚集体（淀粉样蛋白和基于淀粉样蛋白的朊病毒）在哺乳动物（包括人类）和真菌（包括酵母）中发现，并与疾病和遗传性状相关。Hsp104/70/40分子伴侣机制控制酵母朊病毒的繁殖。Hsp70分子伴侣Ssa和Ssb对翻译终止因子Sup35（eRF3）的朊病毒形式[PSI +]表现出相反的作用。Ssb通过由Hsp40-Zuo1和Hsp70-Ssz1组成的核糖体相关复合物（ribosome-associated complex，RAC）与翻译核糖体结合。在这里，我们表明，RAC中断增加从头朊病毒形成的方式类似于SSB耗尽，但干扰朊病毒繁殖的方式类似于SSB过度生产。在RAC缺陷细胞中，Ssb释放到胞质溶胶中拮抗Ssa与淀粉样蛋白的结合。因此，由于缺乏核糖体相关的Ssb而形成的淀粉样蛋白的传播可以被胞质Ssb抵消，产生反馈调节回路。在不良合成培养基中生长期间，在野生型细胞中也观察到Ssb从核糖体的释放。SSB是，在很大程度上，负责在这些条件下的朊病毒不稳定，强调生理相关性的SSB为基础的监管电路。
Cross-beta fibrous protein aggregates (amyloids and amyloid-based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The Hsp104/70/40 chaperone machinery controls propagation of yeast prions. The Hsp70 chaperones Ssa and Ssb show opposite effects on [PSI+], a prion form of the translation termination factor Sup35 (eRF3). Ssb is bound to translating ribosomes via ribosome-associated complex (RAC), composed of Hsp40-Zuo1 and Hsp70-Ssz1. Here we demonstrate that RAC disruption increases de novo prion formation in a manner similar to Ssb depletion, but interferes with prion propagation in a manner similar to Ssb overproduction. Release of Ssb into the cytosol in RAC-deficient cells antagonizes binding of Ssa to amyloids. Thus, propagation of an amyloid formed due to lack of ribosome-associated Ssb can be counteracted by cytosolic Ssb, generating a feedback regulatory circuit. Release of Ssb from ribosomes is also observed in wild type cells during growth in poor synthetic medium. Ssb is, in a significant part, responsible for the prion destabilization in these conditions, underlining the physiological relevance of the Ssb-based regulatory circuit.
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