Hypusination of Eif5a Regulates Cytoplasmic TDP-43 Aggregation and Accumulation in a Stress-Induced Cellular Model

Authors

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

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 (eIF5A^HypK50) 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 eIF5A^HypK50 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 eIF5A^HypK50. These findings are the first to provide a novel pathway and potential therapeutic targets that require further investigation in models of TDP-43 proteinopathies.

Document Type

Article

Publication Date

8-31-2020

Notes/Citation Information

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/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bbadis.2020.165939

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.

Repository Citation

Smeltzer, Shayna; Quadri, Zainuddin; Miller, Abraian; Zamudio, Frank; Hunter, Jordan; Stewart, Nicholas J.F.; Saji, Sheba; Lee, Daniel C.; Chaput, Dale; and Selenica, Maj-Linda B., "Hypusination of Eif5a Regulates Cytoplasmic TDP-43 Aggregation and Accumulation in a Stress-Induced Cellular Model" (2020). Sanders-Brown Center on Aging Faculty Publications. 171.
https://uknowledge.uky.edu/sbcoa_facpub/171