Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation
Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation
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DOI：
10.1038/nsmb.2031
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发表时间：
2011-04-01
影响因子：
16.8
通讯作者：
Serio, Tricia R.
中科院分区：
文献类型：
--
作者：
DiSalvo, Susanne;Derdowski, Aaron;Serio, Tricia R.
蛋白质错误折叠是许多神经退行性疾病的基础，包括传染性海绵状脑病（朊病毒疾病）。虽然细胞通常识别和处理错误折叠的蛋白质，但朊病毒蛋白质通过形成稳定的、自我复制的聚集体来逃避保护措施。然而，显性阴性朊病毒突变体的共表达可以通过目前未知的途径克服积聚和疾病进展。在这里，我们确定了酿酒酵母Sup35蛋白的两个突变体治疗[PSI+]朊病毒的机制。我们发现，这两种突变体都能融入野生型聚集体，并以不同的方式改变它们的物理性质，从而降低它们的组装率或热力学稳定性。尽管野生型聚集体不受细胞干预，但混合聚集体可以被分子伴侣Hsp104分解。因此，显性阴性朊病毒突变体不是简单地阻断错误折叠，而是针对总体生物发生中的多个事件，以增强其对内源性质量控制途径的易感性。
Protein misfolding underlies many neurodegenerative diseases, including the transmissible spongiform encephalopathies (prion diseases). Although cells typically recognize and process misfolded proteins, prion proteins evade protective measures by forming stable, self-replicating aggregates. However, coexpression of dominant-negative prion mutants can overcome aggregate accumulation and disease progression through currently unknown pathways. Here we determine the mechanisms by which two mutants of the Saccharomyces cerevisiae Sup35 protein cure the [PSI+] prion. We show that both mutants incorporate into wild-type aggregates and alter their physical properties in different ways, diminishing either their assembly rate or their thermodynamic stability. Whereas wild-type aggregates are recalcitrant to cellular intervention, mixed aggregates are disassembled by the molecular chaperone Hsp104. Thus, rather than simply blocking misfolding, dominant-negative prion mutants target multiple events in aggregate biogenesis to enhance their susceptibility to endogenous quality-control pathways.