美国耶鲁大学Christian Schlieker和Sarah M. Prophet研究组发现，与神经疾病相关的非典型核膜凝集揭示了核孔蛋白导向的伴侣活性。相关论文于2022年10月27日发表在《自然—细胞生物学》杂志上。

他们报道气泡腔中的FG-核孔蛋白形成异常凝集，并通过激发两种蛋白质毒性损伤导致DYT1肌张力障碍。短寿命的泛素化蛋白通常迅速降解进入气泡腔内并变得稳定。此外，气泡选择性地隔离特定的HSP40-HSP70伴侣网络，该网络由气泡成分MLF2调节。MLF2抑制FG-核孔蛋白的异位积累，调节体外凝聚物的选择性和大小。他们的研究确定了凝集物形成背景下蛋白质毒性的双重机制，并建立了核伴侣网络的FG-核孔蛋白导向活性。

据介绍，DYT1肌张力障碍是一种衰弱性神经运动障碍，由AAA+ atp酶TorsinA突变引起。Torsin功能障碍的标志是由核孔复合体生物形成缺陷引起的核膜气泡。气泡是否正向促进疾病的表现尚不清楚。

附：英文原文

Title: Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities

Author: Prophet, Sarah M., Rampello, Anthony J., Niescier, Robert F., Gentile, Juliana E., Mallik, Sunanda, Koleske, Anthony J., Schlieker, Christian

Issue&Volume: 2022-10-27

Abstract: DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40–HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network.

DOI: 10.1038/s41556-022-01001-y

Source: https://www.nature.com/articles/s41556-022-01001-y