Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)-Induced Cell Death
Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)-Induced Cell Death
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DOI：
10.1002/adbi.202300334
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发表时间：
2024-01-11
期刊：
影响因子：
3.7
通讯作者：
Fan，Yihui
中科院分区：
文献类型：
--
作者：
Chen，Miaomiao;Guo，Xiaohong;Fan，Yihui
重复二肽如聚（脯氨酸-精氨酸）（polyPR）是由C9 orf 72基因中的六核苷酸GGGGCC重复扩增产生的。这些二肽通常被认为是家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的遗传原因。在本研究中，使用异硫氰酸荧光素（FITC）标记的PR 20研究PR 20诱导的细胞死亡。研究结果表明，PR 20诱导的细胞死亡依赖于其核分布，并且可以被称为importazole的核输入抑制剂阻断。进一步的研究表明，BRD 4抑制剂，如JQ-1和I-BET 762，限制了PR 20的细胞质定位，从而降低了其细胞毒性作用。在机制上，BRD 4的抑制导致许多组蛋白表达的增加，导致组蛋白在细胞质中的积累。这些细胞质组蛋白与PR 20结合并限制其在细胞核内的分布。值得注意的是，单独的组蛋白的异位表达足以对用PR 20处理的细胞提供保护。此外，去氧肾上腺素（PE）诱导细胞肥大和组蛋白在细胞质中分布，这也有助于保护细胞免受PR 20诱导的细胞死亡。该研究表明，暂时诱导细胞质组蛋白的存在可能会减轻二肽重复蛋白的神经毒性作用。
Repeat dipeptides such as poly(proline‐arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20‐induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ‐1 and I‐BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20‐induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.