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

doi:10.1016/j.celrep.2021.109376

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

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21 Scopus citations

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.

Original language	English (US)
Article number	109376
Journal	Cell Reports
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.109376
State	Published - Jul 13 2021

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

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Singh, C. R., Glineburg, M. R., Moore, C., Tani, N., Jaiswal, R., Zou, Y., Aube, E., Gillaspie, S., Thornton, M., Cecil, A., Hilgers, M., Takasu, A., Asano, I., Asano, M., Escalante, C. R., Nakamura, A., Todd, P. K., & Asano, K. (2021). Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism. Cell Reports, 36(2), Article 109376. https://doi.org/10.1016/j.celrep.2021.109376

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

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.",

author = "Singh, {Chingakham Ranjit} and Glineburg, {M. Rebecca} and Chelsea Moore and Naoki Tani and Rahul Jaiswal and Ye Zou and Eric Aube and Sarah Gillaspie and Mackenzie Thornton and Ariana Cecil and Madelyn Hilgers and Azuma Takasu and Izumi Asano and Masayo Asano and Escalante, {Carlos R.} and Akira Nakamura and Todd, {Peter K.} and Katsura Asano",

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year = "2021",

month = jul,

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doi = "10.1016/j.celrep.2021.109376",

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Singh, CR, Glineburg, MR, Moore, C, Tani, N, Jaiswal, R, Zou, Y, Aube, E, Gillaspie, S, Thornton, M, Cecil, A, Hilgers, M, Takasu, A, Asano, I, Asano, M, Escalante, CR, Nakamura, A, Todd, PK & Asano, K 2021, 'Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism', Cell Reports, vol. 36, no. 2, 109376. https://doi.org/10.1016/j.celrep.2021.109376

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T1 - Human oncoprotein 5MP suppresses general and repeat-associated non-AUG translation via eIF3 by a common mechanism

AU - Singh, Chingakham Ranjit

AU - Glineburg, M. Rebecca

AU - Moore, Chelsea

AU - Tani, Naoki

AU - Jaiswal, Rahul

AU - Zou, Ye

AU - Aube, Eric

AU - Gillaspie, Sarah

AU - Thornton, Mackenzie

AU - Cecil, Ariana

AU - Hilgers, Madelyn

AU - Takasu, Azuma

AU - Asano, Izumi

AU - Asano, Masayo

AU - Escalante, Carlos R.

AU - Nakamura, Akira

AU - Todd, Peter K.

AU - Asano, Katsura

PY - 2021/7/13

Y1 - 2021/7/13

N2 - 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.

AB - 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.

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

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