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

Shayna Smeltzer, Zainuddin Quadri, Abraian Miller, Frank Zamudio, Jordan Hunter, Nicholas J.F. Stewart, Sheba Saji, Daniel C. Lee, Dale Chaput, Maj Linda B. Selenica

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number165939
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number1
DOIs
StatePublished - Jan 1 2021

Bibliographical note

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

Publisher Copyright:
© 2020 The Author(s)

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Hypusination of Eif5a regulates cytoplasmic TDP-43 aggregation and accumulation in a stress-induced cellular model'. Together they form a unique fingerprint.

Cite this