Super-Enhancer Protects Cells From Toxicity of C9orf72 Poly(proline–arginine) by Inducing the Expression of KPNA2/KPNB1

IF 2.8 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Biochemistry and Function Pub Date : 2025-01-31 DOI:10.1002/cbf.70053

Miaomiao Chen, Henglu Cui, Xiaoyu Zhang, Shuyan Ma, Jinjing Guo, Zhaoxiu Liu, Donghua Gu, Yihui Fan

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引用次数: 0

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Dipeptide repeat (DPR) proteins, such as poly(proline–arginine) (polyPR) generated from G4C2 repeat expansions, have been shown to be highly toxic. In this study, PR20 was labeled with fluorescein isothiocyanate (FITC) to track its cellular localization. Several cell lines demonstrated survival under PR20 treatment by sequestering PR20 in the cytoplasm. Treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death. Mechanistically, KPNA2/KPNB1 interacted with PR20 in the cytoplasm and hindered PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Treatment with JQ1 significantly reduced the protein levels of KPNA2/KPNB1, allowing PR20 to enter the nucleus. Overexpression of KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. Our results indicate that super-enhancers shield cells from PR20 toxicity by upregulating the expression of KPNA2/KPNB1.

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来源期刊

Cell Biochemistry and Function 生物-生化与分子生物学

CiteScore

6.20

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Cell Biochemistry and Function publishes original research articles and reviews on the mechanisms whereby molecular and biochemical processes control cellular activity with a particular emphasis on the integration of molecular and cell biology, biochemistry and physiology in the regulation of tissue function in health and disease. The primary remit of the journal is on mammalian biology both in vivo and in vitro but studies of cells in situ are especially encouraged. Observational and pathological studies will be considered providing they include a rational discussion of the possible molecular and biochemical mechanisms behind them and the immediate impact of these observations to our understanding of mammalian biology.