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

Eun Kyung Lee; Hyeon Ho Kim; Yuki Kuwano; Kotb Abdelmohsen; Subramanya Srikantan; Sarah S. Subaran; Marc Gleichmann; Mohamed R. Mughal; Jennifer L. Martindale; Xiaoling Yang; Paul F. Worley; Mark P. Mattson; Myriam Gorospe

doi:10.1038/nsmb.1815

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

Eun Kyung Lee
, Hyeon Ho Kim
, Yuki Kuwano
, Kotb Abdelmohsen
, Subramanya Srikantan
, Sarah S. Subaran
, Marc Gleichmann
, Mohamed R. Mughal
, Jennifer L. Martindale
, Xiaoling Yang
, Paul F. Worley
, Mark P. Mattson
, Myriam Gorospe

Department of Biochemistry

National Institutes of Health
Johns Hopkins University

Research output: Contribution to journal › Article › peer-review

149 Scopus citations

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.

Original language	English
Pages (from-to)	732-739
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/nsmb.1815
State	Published - Jun 2010

Bibliographical note

Funding Information:
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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Lee, E. K., Kim, H. H., Kuwano, Y., Abdelmohsen, K., Srikantan, S., Subaran, S. S., Gleichmann, M., Mughal, M. R., Martindale, J. L., Yang, X., Worley, P. F., Mattson, M. P., & Gorospe, M. (2010). HnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nature Structural and Molecular Biology, 17(6), 732-739. https://doi.org/10.1038/nsmb.1815

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title = "HnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies",

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.",

author = "Lee, \{Eun Kyung\} and Kim, \{Hyeon Ho\} and Yuki Kuwano and Kotb Abdelmohsen and Subramanya Srikantan and Subaran, \{Sarah S.\} and Marc Gleichmann and Mughal, \{Mohamed R.\} and Martindale, \{Jennifer L.\} and Xiaoling Yang and Worley, \{Paul F.\} and Mattson, \{Mark P.\} and Myriam Gorospe",

note = "Funding Information: 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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AU - Kim, Hyeon Ho

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AU - Abdelmohsen, Kotb

AU - Srikantan, Subramanya

AU - Subaran, Sarah S.

AU - Gleichmann, Marc

AU - Mughal, Mohamed R.

AU - Martindale, Jennifer L.

AU - Yang, Xiaoling

AU - Worley, Paul F.

AU - Mattson, Mark P.

AU - Gorospe, Myriam

N1 - Funding Information: 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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N2 - 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.

AB - 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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JO - Nature Structural and Molecular Biology

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

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