Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism
Chingakham Ranjit Singh,
M. Rebecca Glineburg,
Chelsea Moore,
Naoki Tani,
Rahul Jaiswal,
Ye Zou,
Eric Aube,
Sarah Gillaspie,
Mackenzie Thornton,
Ariana Cecil,
Madelyn Hilgers,
Azuma Takasu,
Izumi Asano,
Masayo Asano,
Carlos R. Escalante,
Akira Nakamura,
Peter K. Todd,
Katsura Asano
Affiliations
Chingakham Ranjit Singh
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
M. Rebecca Glineburg
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
Chelsea Moore
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Naoki Tani
Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
Rahul Jaiswal
Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
Ye Zou
Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA
Eric Aube
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Sarah Gillaspie
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Mackenzie Thornton
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Ariana Cecil
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Madelyn Hilgers
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Azuma Takasu
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Izumi Asano
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Masayo Asano
Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Carlos R. Escalante
Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
Akira Nakamura
Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
Peter K. Todd
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Ann Arbor VA Medical Center, Ann Arbor, MI 48105, USA
Katsura Asano
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; Corresponding author
Summary: 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.
