Autophagy protects against de novo formation of the [PSI+] prion in yeast.
Autophagy protects against de novo formation of the [PSI+] prion in yeast.
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DOI：
10.1091/mbc.e15-08-0548
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发表时间：
2015-12-15
影响因子：
3.3
通讯作者：
Grant CM
中科院分区：
文献类型：
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作者：
Speldewinde SH;Doronina VA;Grant CM
普鲁恩自发产生的分子基础还知之甚少。目前的数据表明，氧化蛋白质损伤是从头蛋白形成的触发因素之一。自噬的功能是在氧化损伤的蛋白质转化为Pron形式之前将其清除。Prion是一种自我繁殖的感染性蛋白质，是几种神经退行性疾病的基础。它们零星形成的分子基础还知之甚少。我们发现，自噬可以防止[PSI+]的从头形成，[PSI+]是酵母Sup35翻译终止因子的Prion形式。自噬是一种细胞降解系统，通过突变其核心成分来防止自噬会提高自发形成[PSI+]的频率。相反，通过用多胺亚精胺处理细胞来增加自噬通量，可以抑制突变株中的Pron形成，而突变株通常表现出高频率的从头Pron形成。自噬还可以防止另一种Prion的从头形成，即Rnq1/[PIN+]Prion，它与Sup35/[Psi+]Prion的序列不相关。我们表明，在没有分子氧的厌氧条件下生长可以消除Sup35蛋白的损伤，并抑制自噬突变体中[PSI+]的高频形成。因此，自噬通常起到去除氧化损伤的Sup35的作用，Sup35在有氧条件下生长的细胞中积累，但在没有自噬的情况下，损坏/错误折叠的Sup35经历有利于其转换为可繁殖的[PSI+]形式的结构转变。
The molecular basis by which prions arise spontaneously is poorly understood. The present data point toward oxidative protein damage as one of the triggers of de novo prion formation. Autophagy functions to clear oxidatively damaged proteins before their conversion to the prion form. Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [PSI+], which is the prion form of the yeast Sup35 translation termination factor. Autophagy is a cellular degradation system, and preventing autophagy by mutating its core components elevates the frequency of spontaneous [PSI+] formation. Conversely, increasing autophagic flux by treating cells with the polyamine spermidine suppresses prion formation in mutants that normally show a high frequency of de novo prion formation. Autophagy also protects against the de novo formation of another prion, namely the Rnq1/[PIN+] prion, which is not related in sequence to the Sup35/[PSI+] prion. We show that growth under anaerobic conditions in the absence of molecular oxygen abrogates Sup35 protein damage and suppresses the high frequency of [PSI+] formation in an autophagy mutant. Autophagy therefore normally functions to remove oxidatively damaged Sup35, which accumulates in cells grown under aerobic conditions, but in the absence of autophagy, damaged/misfolded Sup35 undergoes structural transitions favoring its conversion to the propagatable [PSI+] form.