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.
Chingakham Ranjit Singh, M. Rebecca Glineburg, Chelsea Moore, Rahul Jaiswal, Sarah Gilaspie, Eric Aube, Ye Zou, Mackenzie Thornton, Ariana Cecil, Madelyn Hilgers, Carlos Escalente, Peter Todd, and Katsura Asano, “Human oncoprotein 5MP1 suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism” Cell Reports. 2021 July 13;36(2):109376. https://doi.org/10.1016/j.celrep.2021.109376
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