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

Miyuki Hayashi, Amandeep Girdhar, Ying-Hui Ko, Kevin M. Kim, Jacquelyn A. DePierro, Joseph R. Buchler, Nikhita Arunprakash, Aditya Bajaj, Gino Cingolani () and Lin Guo ()
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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
Nikhita Arunprakash: Thomas Jefferson University
Aditya Bajaj: Thomas Jefferson University
Gino Cingolani: The University of Alabama at Birmingham
Lin Guo: Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52151-6

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