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PMID: 20473314 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

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

Nature structural & molecular biology ·Vol. 17 ·No. 6 ·2010-06-00 ·Pages 732-9

Lee EK, Kim HH, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran SS, Gleichmann M, Mughal MR, Martindale JL, Yang X, Worley PF, Mattson MP, Gorospe M

Abstract

Amyloid precursor protein (APP) regulates neuronal synapse function, and its cleavage product Abeta 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.

MeSH Terms
3' Untranslated Regions Alzheimer Disease/genetics,metabolism Amyloid beta-Protein Precursor/biosynthesis,genetics Animals Base Sequence Binding, Competitive Cell Line Cytoplasmic Structures/metabolism Fragile X Mental Retardation Protein/genetics,metabolism Genes, Reporter Green Fluorescent Proteins/genetics Heterogeneous-Nuclear Ribonucleoprotein Group C/metabolism Humans In Vitro Techniques Mice Mice, Knockout Models, Biological Molecular Sequence Data Neurons/metabolism Protein Biosynthesis RNA, Messenger/genetics,metabolism RNA, Small Interfering/genetics Recombinant Proteins/genetics
Chemicals
3' Untranslated Regions Amyloid beta-Protein Precursor FMR1 protein, human Fmr1 protein, mouse Heterogeneous-Nuclear Ribonucleoprotein Group C RNA, Messenger RNA, Small Interfering Recombinant Proteins enhanced green fluorescent protein Fragile X Mental Retardation Protein Green Fluorescent Proteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Lee Eun Kyung
Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA.
Kim Hyeon Ho
Kuwano Yuki
Abdelmohsen Kotb
Srikantan Subramanya
Subaran Sarah S
Gleichmann Marc
Mughal Mohamed R
Martindale Jennifer L
Yang Xiaoling
Worley Paul F
Mattson Mark P
Gorospe Myriam
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1815
Published
2010-06-00
Epub
2010-00-16
Pages
732-9
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2908492
Subset
IM
Grants
NIDA NIH HHS · P50 DA000266 · United States
Intramural NIH HHS · Z01 AG000518-04 · United States
NIDA NIH HHS · DA00266 · United States
Corrections
CommentIn
PMID: 20520660
External Links
PubMed source DOI: 10.1038/nsmb.1815 PMC Full Text View journal details
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