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

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.