精氨酸脱氨酶 4 通过调节 FET 蛋白中 RGG 基序的瓜氨酸化来调节蛋白聚集和肌萎缩侧索硬化症易感性。
Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility.
机构信息
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Project for Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Tokyo 135-8550, Japan.
出版信息
Cell Rep. 2018 Feb 6;22(6):1473-1483. doi: 10.1016/j.celrep.2018.01.031.
Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4 mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis.
最近的蛋白质组分析提供了对各种翻译后修饰（PTMs）的全面概述；然而，涉及蛋白质瓜氨酸化的 PTM 仍然不清楚。我们进行了瓜氨酸化蛋白质的蛋白质组分析，鉴定了超过 100 个 PAD4（肽精氨酸脱亚氨酶 4）底物。大约五分之一的 PAD4 底物含有 RG/RGG 基序，PAD4 竞争性抑制 FET 蛋白（FUS、EWS 和 TAF15）和 hnRNPA1 中 RGG 基序的甲基化，FET 蛋白和 hnRNPA1 是 ALS（肌萎缩侧索硬化症）的致病基因。PAD4 介导的瓜氨酸化显著抑制 FET 蛋白的聚集，这是神经退行性疾病中常见的特征。在砷诱导的应激颗粒中，FUS 蛋白水平在 Padi4 小鼠胚胎成纤维细胞（MEFs）中显著增加。此外，rs2240335 与大脑中 PADI4 的低表达和 ALS 的高风险相关（p = 0.0381，优势比为 1.072）。我们的研究结果表明，PAD4 介导的 RGG 瓜氨酸化在蛋白质可溶性和 ALS 发病机制中起关键作用。
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