TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA/DNA binding protein involved in mRNA metabolism. Aberrant mislocalization to the cytoplasm and formation of phosphorylated/aggregated TDP-43 inclusions remains the hallmark pathology in a spectrum of neurodegenerative diseases, including frontotemporal disorders and Alzheimer's disease. Eukaryotic Translation Initiation Factor 5A undergoes a unique post-translation modification of lysine to hypusine (K50), which determines eIF5A binding partners. We used a sodium arsenite-induced cellular stress model to investigate the role of hypusinated eIF5A (eIF5AHypK50) in governing TDP-43 cytoplasmic mislocalization and accumulation in stress granule. Our proteomics and functional data provide evidence that eIF5A interacts with TDP-43 in a hypusine-dependent manner. Additionally, we showed that following stress TDP-43 interactions with eIF5AHypK50 were induced both in the cytoplasm and stress granules. Pharmacological reduction of hypusination or mutations of lysine residues within the hypusine loop decreased phosphorylated and insoluble TDP-43 levels. The proteomic and biochemical analysis also identified nuclear pore complex importins KPNA1/2, KPNB1, and RanGTP as interacting partners of eIF5AHypK50. These findings are the first to provide a novel pathway and potential therapeutic targets that require further investigation in models of TDP-43 proteinopathies.

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Published in Biochimica et Biophysica Acta (BBA)- Molecular Basis of Disease, v. 1867, issue 1, 165939.

© 2020 The Author(s)

The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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This work was supported by the College of Pharmacy Start-up Funds and COP New Investigator Seed Grant, University of South Florida FL, USA.

1-s2.0-S0925443920302878-mmc1.docx (27 kB)
Supplementary Table 1. Top 50 proteins identified in co-IP with eIF5AHypK50 by MS.

1-s2.0-S0925443920302878-mmc2.docx (15 kB)
Supplementary Table 2. Top twenty molecular functions were assigned using EBI Gene Ontology Database (GOA).

1-s2.0-S0925443920302878-mmc3.docx (15 kB)
Supplementary Table 3. Top twenty biological processes were assigned using EBI Gene Ontology Database (GOA).

1-s2.0-S0925443920302878-mmc4.xlsx (14 kB)
Supplementary Table 4. List of antibodies and drugs used in this study, corresponding catalog numbers, dilutions, companies, and protein targets or function.