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hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies

Nature Structural & Molecular Biology volume 17, pages 732–739 (2010)Cite this article

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Abstract

Amyloid precursor protein (APP) regulates neuronal synapse function, and its cleavage product Aβ is linked to Alzheimer's disease. Here, we present evidence that the RNA-binding proteins (RBPs) heterogeneous nuclear ribonucleoprotein (hnRNP) C and fragile X mental retardation protein (FMRP) associate with the same APP mRNA coding region element, and they influence APP translation competitively and in opposite directions. Silencing hnRNP C increased FMRP binding to APP mRNA and repressed APP translation, whereas silencing FMRP enhanced hnRNP C binding and promoted translation. Repression of APP translation was linked to colocalization of FMRP and tagged APP RNA within processing bodies; this colocalization was abrogated by hnRNP C overexpression or FMRP silencing. Our findings indicate that FMRP represses translation by recruiting APP mRNA to processing bodies, whereas hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block.

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Figure 1: hnRNP C and FMRP interact with the coding region of APP mRNA.
Figure 2: Effect of silencing hnRNP C and FMRP on APP expression.
Figure 3: hnRNP C modestly reduces APP expression levels through the APP 3′ UTR.
Figure 4: hnRNP C and FMRP control APP levels through the APP CR(C).
Figure 5: hnRNP C and FMRP bind the APP CR(C) competitively.
Figure 6: APP mRNA interacts with components of processing bodies.
Figure 7: APP RNA colocalizes with PBs in an FMRP– and hnRNP C–dependent manner.
Figure 8: Model of competition between FMRP and hnRNP C to modulate APP translation.

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Acknowledgements

We thank F.E. Indig and M.H. Dehoff for assistance with experiments. This research was supported by the National Institute on Aging-Intramural Research Program, US National Institutes of Health. P.F.W. is suppported by DA00266.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA

    Eun Kyung Lee, Hyeon Ho Kim, Yuki Kuwano, Kotb Abdelmohsen, Subramanya Srikantan, Jennifer L Martindale, Xiaoling Yang & Myriam Gorospe

  2. Confocal Imaging Facility, Research Resources Branch, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA

    Sarah S Subaran

  3. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA

    Marc Gleichmann, Mohamed R Mughal & Mark P Mattson

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Paul F Worley

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Contributions

E.K.L., H.H.K., K.A., J.L.M., X.Y., M.P.M. and M. Gorospe designed the study; E.K.L., H.H.K., Y. K., K.A., S.S., S.S.S., J.L.M. and X.Y. performed the experiments; E.K.L., Y. K., M. Gleichmann, M.R.M., X.Y., P.F.W. and M.P.M. contributed key reagents; E.K.L., M.P.M. and M. Gorospe wrote the paper.

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Correspondence to Myriam Gorospe.

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Lee, E., Kim, H., Kuwano, Y. et al. hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nat Struct Mol Biol 17, 732–739 (2010). https://doi.org/10.1038/nsmb.1815

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