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Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS

Author

Listed:
  • Miyuki Hayashi

    (Thomas Jefferson University)

  • Amandeep Girdhar

    (Thomas Jefferson University)

  • Ying-Hui Ko

    (The University of Alabama at Birmingham)

  • Kevin M. Kim

    (Thomas Jefferson University)

  • Jacquelyn A. DePierro

    (Thomas Jefferson University)

  • Joseph R. Buchler

    (Thomas Jefferson University
    Thomas Jefferson University)

  • Nikhita Arunprakash

    (Thomas Jefferson University)

  • Aditya Bajaj

    (Thomas Jefferson University)

  • Gino Cingolani

    (The University of Alabama at Birmingham)

  • Lin Guo

    (Thomas Jefferson University)

Abstract

Importin β-superfamily nuclear import receptors (NIRs) mitigate mislocalization and aggregation of RNA-binding proteins (RBPs), like FUS and TDP-43, which are implicated in neurodegenerative diseases. NIRs potently disaggregate RBPs by recognizing their nuclear localization signal (NLS). However, disease-causing mutations in NLS compromise NIR binding and activity. Here, we define features that characterize the anti-aggregation activity of NIR and NLS. We find that high binding affinity between NIR and NLS, and optimal NLS location relative to the aggregating domain plays a role in determining NIR disaggregation activity. A designed FUS chimera (FUSIBB), carrying the importin β binding (IBB) domain, is solubilized by importin β in vitro, translocated to the nucleus in cultured cells, and downregulates the expression of endogenous FUS. In this study, we posit that guiding the mutual recognition of NLSs and NIRs will aid the development of therapeutics, illustrated by the highly soluble FUSIBB replacing the aggregation-prone endogenous FUS.

Suggested Citation

  • Miyuki Hayashi & Amandeep Girdhar & Ying-Hui Ko & Kevin M. Kim & Jacquelyn A. DePierro & Joseph R. Buchler & Nikhita Arunprakash & Aditya Bajaj & Gino Cingolani & Lin Guo, 2024. "Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52151-6
    DOI: 10.1038/s41467-024-52151-6
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    References listed on IDEAS

    as
    1. Hermann Broder Schmidt & Ariana Barreau & Rajat Rohatgi, 2019. "Phase separation-deficient TDP43 remains functional in splicing," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Yu-Sheng Fang & Kuen-Jer Tsai & Yu-Jen Chang & Patricia Kao & Rima Woods & Pan-Hsien Kuo & Cheng-Chun Wu & Jhih-Ying Liao & Shih-Chieh Chou & Vinson Lin & Lee-Way Jin & Hanna S. Yuan & Irene H. Cheng , 2014. "Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
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