Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism

  • Cell Rep. 2021 Jul 13;36(2):109376. doi: 10.1016/j.celrep.2021.109376.
Chingakham Ranjit Singh  1 ,  M Rebecca Glineburg  2 ,  Chelsea Moore  1 ,  Naoki Tani  3 ,  Rahul Jaiswal  4 ,  Ye Zou  5 ,  Eric Aube  1 ,  Sarah Gillaspie  1 ,  Mackenzie Thornton  1 ,  Ariana Cecil  1 ,  Madelyn Hilgers  1 ,  Azuma Takasu  1 ,  Izumi Asano  1 ,  Masayo Asano  1 ,  Carlos R Escalante  4 ,  Akira Nakamura  3 ,  Peter K Todd  6 ,  Katsura Asano  7
Affiliations
  • 1. Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
  • 2. Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3. Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
  • 4. Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
  • 5. Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA.
  • 6. Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Ann Arbor VA Medical Center, Ann Arbor, MI 48105, USA.
  • 7. Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA; Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan; Hiroshima Research Center for Healthy Aging, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan. Electronic address: [email protected].
PMID: 34260931 DOI: 10.1016/j.celrep.2021.109376
Abstract

eIF5-mimic protein (5MP) is a translational regulatory protein that binds the small ribosomal subunit and modulates its activity. 5MP is proposed to reprogram non-AUG translation rates for oncogenes in Cancer, but its role in controlling non-AUG initiated synthesis of deleterious repeat-peptide products, such as FMRpolyG observed in fragile-X-associated tremor ataxia syndrome (FXTAS), is unknown. Here, we show that 5MP can suppress both general and repeat-associated non-AUG (RAN) translation by a common mechanism in a manner dependent on its interaction with eIF3. Essentially, 5MP displaces eIF5 through the eIF3c subunit within the preinitiation complex (PIC), thereby increasing the accuracy of initiation. In Drosophila, 5MP/Kra represses neuronal toxicity and enhances the lifespan in an FXTAS disease model. These results implicate 5MP in protecting cells from unwanted byproducts of non-AUG translation in neurodegeneration.

Keywords
FXTAS; RAN translation; cancer; eIF5-mimic protein; non-AUG start codon; ribosome; translation initiation.