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热休克伴侣HSPB1调控细胞质TDP-43相分离和液态到凝胶的转变
作者:小柯机器人 发布时间:2022/9/11 21:33:23

美国加州大学Don W. Cleveland团队近期取得重要工作进展,他们研究发现热休克伴侣HSPB1调节细胞质TDP-43的相分离和液态到凝胶的转变。相关论文2022年9月8日在线发表于《自然—细胞生物学》杂志上。

研究人员表明,瞬时氧化应激、蛋白酶体抑制或HSP70的ATP依赖性伴侣活性的抑制,引起可逆的细胞质TDP-43分离和从液体到凝胶/固体的转变,这一现象与TDP43的RNA结合功能或应激颗粒无关。同位素标记质谱法用于鉴定相分离的细胞质TDP-43与小热休克蛋白 HSPB1 结合。TDP-43与HSPB1的结合是直接的,通过TDP-43的RNA结合和低复杂性结构域介导。

HSPB1分隔成TDP-43液滴,抑制TDP-43组装成原纤维,并且对于压力诱导的TDP-43液滴的拆卸至关重要。HSPB1的减少促进了细胞质TDP-43的分离和错误定位。在含有聚集TDP-43的ALS患者的脊髓运动神经元中发现HSPB1耗竭。这些发现确定HSPB1是细胞质TDP-43相分离和聚集的调节剂。

据介绍,虽然乙酰化,RNA结合缺陷的TDP-43在核内可逆地相分离成复杂的液滴,包括含有TDP-43的液体外壳和HSP70家族伴侣的液体中心,TDP-43的细胞质聚集是多种神经退行性疾病的标志,包括肌萎缩性侧索硬化症(ALS)。

附:英文原文

Title: Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition

Author: Lu, Shan, Hu, Jiaojiao, Arogundade, Olubankole Aladesuyi, Goginashvili, Alexander, Vazquez-Sanchez, Sonia, Diedrich, Jolene K., Gu, Jinge, Blum, Jacob, Oung, Spencer, Ye, Qiaozhen, Yu, Haiyang, Ravits, John, Liu, Cong, Yates, John R., Cleveland, Don W.

Issue&Volume: 2022-09-08

Abstract: While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

DOI: 10.1038/s41556-022-00988-8

Source: https://www.nature.com/articles/s41556-022-00988-8

期刊信息

Nature Cell Biology:《自然—细胞生物学》,创刊于1999年。隶属于施普林格·自然出版集团,最新IF:20.042
官方网址:https://www.nature.com/ncb/
投稿链接:https://mts-ncb.nature.com/cgi-bin/main.plex