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Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS
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Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS
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Journal Article
Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS
2024
Overview
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 (FUS
IBB
), 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 FUS
IBB
replacing the aggregation-prone endogenous FUS.
This study developed a FUS chimera (FUSIBB) with a highly efficient anti-aggregation signal that is engaged by a nuclear import receptor, Importin beta. FUSIBB can mitigate aggregation and reduce expression of a neurodegeneration-linked protein, FUS.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/109
/ 14/63
/ 147/143
/ 82/80
/ 82/83
/ Active Transport, Cell Nucleus
/ Amyotrophic lateral sclerosis
/ beta Karyopherins - genetics
/ beta Karyopherins - metabolism
/ Binding
/ Chimeras
/ Humanities and Social Sciences
/ Humans
/ Imports
/ Mutation
/ Nuclear Localization Signals
/ Proteins
/ Recombinant Fusion Proteins - genetics
/ Recombinant Fusion Proteins - metabolism
/ RNA-Binding Protein FUS - genetics
/ RNA-Binding Protein FUS - metabolism
/ Science
/ Toxicity
