蛋白质二硫键异构酶
伴侣(临床)
S-亚硝基化
内质网
胞浆
化学
生物化学
蛋白质折叠
半胱氨酸
亚硝化
蛋白质聚集
细胞生物学
热休克蛋白70
未折叠蛋白反应
神经退行性变
热休克蛋白
突变体
异构酶
化学伴侣
酶
生物
有机化学
病理
一氧化氮
基因
医学
疾病
作者
Kan Wang,Jiaqi Liu,Tao Zhong,Xiaoling Liu,Yan Zeng,X. K. Qiao,Ting Xie,Yu‐Zhe Chen,Yingying Gao,Bo Tang,Jia Li,Jun Zhou,Dai‐Wen Pang,Jing Chen,Chang Chen,Yi Liang
标识
DOI:10.1016/j.jmb.2020.02.013
摘要
Cells have evolved molecular chaperones that modulate phase separation and misfolding of amyloidogenic proteins to prevent neurodegenerative diseases. Protein disulfide isomerase (PDI), mainly located at the endoplasmic reticulum and also present in the cytosol, acts as both an enzyme and a molecular chaperone. PDI is observed to be S-nitrosylated in the brain of Alzheimer's disease patients, but the mechanism has remained elusive. We herein report that both wild-type PDI and its quadruple cysteine mutant only having chaperone activity, significantly inhibit pathological phosphorylation and abnormal aggregation of Tau in cells, and significantly decrease the mitochondrial damage and Tau cytotoxicity resulting from Tau aberrant aggregation, highlighting the chaperone property of PDI. More importantly, we show that wild-type PDI is selectively recruited by liquid droplets of Tau, which significantly inhibits phase separation and stress granule formation of Tau, whereas S-nitrosylation of PDI abrogates the recruitment and inhibition. These findings demonstrate how phase separation of Tau is physiologically regulated by PDI and how S-nitrosylation of PDI, a perturbation in this regulation, leads to disease.
科研通智能强力驱动
Strongly Powered by AbleSci AI