hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies.
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.
Lee
Eun Kyung
EK
Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA.
Kim
Hyeon Ho
HH
Kuwano
Yuki
Y
Abdelmohsen
Kotb
K
Srikantan
Subramanya
S
Subaran
Sarah S
SS
Gleichmann
Marc
M
Mughal
Mohamed R
MR
Martindale
Jennifer L
JL
Yang
Xiaoling
X
Worley
Paul F
PF
Mattson
Mark P
MP
Gorospe
Myriam
M
D020413:3' Untranslated Regions; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D022083:Cytoplasmic Structures / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics
D020413:3' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse; C485184:enhanced green fluorescent protein
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