Kabani Mehdi
Institut de Biologie François Jacob, Molecular Imaging Research Center (MIRCen), Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Laboratoire des Maladies Neurodégénératives, Centre National de la Recherche Scientifique (CNRS), F-92265 Fontenay-aux-Roses.
Microb Cell. 2020 Jun 2;7(7):199-201. doi: 10.15698/mic2020.07.724.
Infectious proteins or prions are non-native conformations of proteins that are the causative agents of devastating neurodegenerative diseases in humans and heritable traits in filamentous fungi and yeasts. Prion proteins form highly ordered self-perpetuating fibrillar aggregates that traffic vertically and horizontally from cell to cell. The spreading of these infectious entities relies on different mechanisms, among which the extracellular vesicles (EV)-mediated traffic. The prion form of the yeast Sup35p translation terminator causes the [ ] nonsense suppression phenotype. This fascinating biological model helped us shape our understanding of the mechanisms of formation, propagation and elimination of infectious protein aggregates. We discovered that Sup35p is exported via EV, both in its soluble and aggregated infectious states. We recently reported that high amounts of Sup35p prion particles are exported to the yeast periplasm via periplasmic vesicles (PV) in glucose-starved cells. EV and PV are different in terms of size and protein content, and their export is inversely regulated by glucose availability in the growth medium. We believe these are important observations that should make us revise our current view on the way yeast prions propagate. Hence, I propose several hypotheses as to the significance of these observations for the transmission of yeast prions. I also discuss how yeast could be used as a powerful tractable biological model to investigate the molecular mechanisms of vesicle-mediated export of pathological protein aggregates implicated in neurodegenerative diseases.
感染性蛋白质或朊病毒是蛋白质的非天然构象，是人类毁灭性神经退行性疾病以及丝状真菌和酵母中可遗传性状的致病因子。朊病毒蛋白形成高度有序的自我延续的纤维状聚集体，可在细胞间垂直和水平传播。这些感染性实体的传播依赖于不同机制，其中包括细胞外囊泡（EV）介导的运输。酵母Sup35p翻译终止子的朊病毒形式会导致[ ]无义抑制表型。这个引人入胜的生物学模型帮助我们形成了对感染性蛋白质聚集体的形成、传播和消除机制的理解。我们发现，Sup35p在其可溶性和聚集感染状态下均通过EV输出。我们最近报道，在葡萄糖饥饿的细胞中，大量Sup35p朊病毒颗粒通过周质囊泡（PV）输出到酵母周质中。EV和PV在大小和蛋白质含量方面有所不同，它们的输出受生长培养基中葡萄糖可用性的反向调节。我们认为这些重要发现应促使我们修正目前对酵母朊病毒传播方式的看法。因此，我就这些发现对酵母朊病毒传播的意义提出了几个假设。我还讨论了如何将酵母用作强大的易处理生物学模型，以研究与神经退行性疾病相关的病理蛋白质聚集体的囊泡介导输出的分子机制。
