TY - JOUR
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
N1 - Funding Information:
We thank Hitomi Yagi (Kindai University, Japan), Takuya Ohshima (Kindai University, Japan), and Rho Murakami (Niigata University, Japan) for technical help on yeast assays and Indranil Malik (University of Michigan) for assistance with Drosophila life-span assays. This work was supported by a pilot grant from the K-INBRE program (P20 GM103418), National Institutes of Health ; Innovative Research Awards from the Kansas State University (KSU) Terry Johnson Cancer Center; National Science Foundation research grant ( 1412250 ); National Institutes of Health grant ( GM125671 ); a grant from the Joint Usage/Research Center for Developmental Medicine, IMEG, Kumamoto University , and JSPS International Collaboration Enhancement Award ( 18K19963) to K.A.; by KSU Arts and Science Research Scholarship to M.H., A.C., A.T., and E.A.; by K-INBRE semester scholarship ( P20 GM103418) to S.G., E.A., M.H., and M.T; by K-INBRE Star Trainee program ( P20 GM103418) to C.M. and M.T.; by Goldwater Scholarship to M.T.; by National Institutes of Health grants ( NS099280 , NS086810 , and P50HD104463 ) and a VA grant ( BLRD BX004842) to P.K.T. and by National Institutes of Health T32NS00722237 to M.R.G.; and M.R.G. was supported by the A2A3 Susan Ross award.
Funding Information:
We thank Hitomi Yagi (Kindai University, Japan), Takuya Ohshima (Kindai University, Japan), and Rho Murakami (Niigata University, Japan) for technical help on yeast assays and Indranil Malik (University of Michigan) for assistance with Drosophila life-span assays. This work was supported by a pilot grant from the K-INBRE program (P20 GM103418), National Institutes of Health; Innovative Research Awards from the Kansas State University (KSU) Terry Johnson Cancer Center; National Science Foundation research grant (1412250); National Institutes of Health grant (GM125671); a grant from the Joint Usage/Research Center for Developmental Medicine, IMEG, Kumamoto University, and JSPS International Collaboration Enhancement Award (18K19963) to K.A.; by KSU Arts and Science Research Scholarship to M.H. A.C. A.T. and E.A.; by K-INBRE semester scholarship (P20 GM103418) to S.G. E.A. M.H. and M.T; by K-INBRE Star Trainee program (P20 GM103418) to C.M. and M.T.; by Goldwater Scholarship to M.T.; by National Institutes of Health grants (NS099280, NS086810, and P50HD104463) and a VA grant (BLRD BX004842) to P.K.T. and by National Institutes of Health T32NS00722237 to M.R.G.; and M.R.G. was supported by the A2A3 Susan Ross award. Conceptualization, C.R.S. M.R.G. C.M. P.K.T. and K.A.; methodology, C.R.S. M.R.G. N.T. Y.Z. C.R.E. P.K.T. and K.A.; investigation, C.R.S. M.R.G. C.M. N.T. R.J. Y.Z. E.A. S.G. M.T. A.C. M.H. A.T. I.A. M.A. and K.A.; writing ? original draft, C.R.S. M.R.G. C.M. Y.Z. and K.A.; writing ? review & editing, M.R.G. P.K.T. and K.A.; visualization, C.R.S. M.R.G. Y.Z. and K.A.; funding acquisition, M.R.G. C.R.E. A.N. P.K.T. and K.A.; resources, N.T. A.N. P.K.T. and K.A.; supervision, C.R.E. A.N. P.K.T. and K.A; project administration, K.A. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects.
Publisher Copyright:
© 2021 The Authors
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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U2 - 10.1016/j.celrep.2021.109376
DO - 10.1016/j.celrep.2021.109376
M3 - Article
C2 - 34260931
AN - SCOPUS:85109863938
SN - 2211-1247
VL - 36
JO - Cell Reports
JF - Cell Reports
IS - 2
M1 - 109376
ER -