Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export

• DOI: 10.1016/j.celrep.2022.111106
• Publication Date: 2022-07-19T22:26:43Z
• Authors: Lauren Duan; Benjamin L. Zaepfel; Vasilisa Aksenova; Mary Dasso; Jeffrey D. Rothstein; Petr Kalab; Lindsey R. Hayes
• Keywords: Nuclear export signal; Transcription

Nuclear clearance of the RNA-binding protein TDP-43 is a hallmark neurodegeneration and an important therapeutic target. Our current understanding nucleocytoplasmic transport does not fully explain its predominantly nuclear localization or mislocalization in disease. Here, we show that exits nuclei by passive diffusion, independent facilitated mRNA export. RNA polymerase II blockade RNase treatment induce efflux, suggesting RNAs sequester limit availability for Induction efflux short, GU-rich oligomers (presumably outcompeting binding to endogenous RNAs), retention conferred splicing inhibition, demonstrate depends on RNAs. Indeed, domain mutations markedly reduce abolish transcription blockade-induced efflux. Thus, abundance GU-RNAs, dictated balance transcription, pre-mRNA processing, export, regulates localization.