biostudies-literatureSingh CRBLRD VANICHD NIH HHSNINDS NIH HHSNIGMS NIH HHS109376https://www.ebi.ac.uk/biostudies/studies/S-EPMC8363759biostudies-literatureUnknown36(2)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.Cell reportsHuman oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism.PMC8363759R01 NS099280P20 GM103418I01 BX004842R15 GM124671R01 NS086810R01 GM064781R01 GM124204P50 HD104463Asano MTakasu ATodd PKAsano IEscalante CRAsano KGillaspie SNakamura AZou YJaiswal RThornton MHilgers MAube ESingh CRTani NMoore CCecil AGlineburg MRfalseHuman oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism.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.2021-01-01T00:00:00Z2021 Jul2024-11-13T04:13:27.806Z2022-02-11T08:08:03.381ZS-EPMC83637593426093110.1016/j.celrep.2021.109376