Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the preferential death of motor neurons. Approximately 10% of ALS cases are familial and 90% are sporadic. Fused in Sarcoma (FUS) is a ubiquitously expressed RNA binding protein implicated in familial ALS and frontotemporal dementia (FTD). The physiological function and pathological mechanism of FUS are not well understood, particularly whether post-translational modifications play a role in regulating FUS function. In this study, we discovered that FUS was acetylated at lysine-315/316 (K315/K316) and lysine-510 (K510) residues in two distinct domains. Located in the nuclear localization sequence, K510 acetylation disrupted the interaction between FUS and Transportin-1, resulting in the mis-localization of FUS in the cytoplasm and formation of stress granule-like inclusions. Located in the RNA recognition motif, K315/K316 acetylation reduced RNA binding to FUS and decreased the formation of cytoplasmic inclusions. Treatment with deacetylase inhibitors also significantly reduced the inclusion formation in cells expressing ALS mutation P525L. More interestingly, familial ALS patient fibroblasts showed higher levels of FUS K510 acetylation as compared to healthy controls. Lastly, CBP/p300 acetylated FUS, whereas both SIRT and HDAC families of lysine deacetylases contributed to FUS deacetylation. These findings demonstrate that FUS acetylation regulates the RNA binding, subcellular localization, and inclusion formation of FUS, implicating a potential role of acetylation in the pathophysiological process leading to FUS-mediated ALS/FTD.

中文翻译：

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赖氨酸乙酰化调节 FUS 的 RNA 结合、亚细胞定位和包涵体形成。

肌萎缩侧索硬化 (ALS) 是一种神经退行性疾病，其特征是运动神经元优先死亡。大约 10% 的 ALS 病例是家族性的，90% 是散发性的。融合肉瘤 (FUS) 是一种普遍表达的 RNA 结合蛋白，与家族性 ALS 和额颞叶痴呆 (FTD) 相关。FUS 的生理功能和病理机制尚不清楚，特别是翻译后修饰是否在调节 FUS 功能中发挥作用。在这项研究中，我们发现 FUS 在两个不同结构域中的 lysine-315/316 (K315/K316) 和 lysine-510 (K510) 残基处被乙酰化。位于核定位序列中，K510 乙酰化破坏了 FUS 和 Transportin-1 之间的相互作用，导致 FUS 在细胞质中的错误定位和应力颗粒状内含物的形成。位于 RNA 识别基序中，K315/K316 乙酰化减少了 RNA 与 FUS 的结合并减少了细胞质内含物的形成。用脱乙酰酶抑制剂处理也显着减少了表达 ALS 突变 P525L 的细胞中的包涵体形成。更有趣的是，与健康对照相比，家族性 ALS 患者成纤维细胞显示出更高水平的 FUS K510 乙酰化。最后，CBP/p300 乙酰化 FUS，而赖氨酸脱乙酰酶的 SIRT 和 HDAC 家族都有助于 FUS 脱乙酰。这些发现表明 FUS 乙酰化调节 FUS 的 RNA 结合、亚细胞定位和包涵体形成，