Hypusination of Eif5a regulates cytoplasmic TDP-43 aggregation and accumulation in a stress-induced cellular model

https://doi.org/10.1016/j.bbadis.2020.165939Get rights and content
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Highlights

  • Hypusinated eIF5A regulates the TDP-43 sequestration and accumulation to the cytoplasm.

  • Hypusinated eIF5A governs TDP-43 accumulation in stress granule.

  • Nucleocytoplasmic transport cargo molecules interact with eIF5A in hypusine-dependent fashion.

  • Mutations in K50 and pharmacological reduction of hypusine levels alleviatsTDP-43 cytoplasmic sequestration and aggregation.

Abstract

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.

Keywords

eIF5A
Hypusination
TDP-43
Cytoplasmic accumulation
Stress granule
Nuclear import
Proteinopathy

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