Dendritic BC1 RNA: functional role in regulation of translation initiation.
In neurons, local protein synthesis in synaptodendritic microdomains has been implicated in the growth and plasticity of synapses. Prerequisites for local translation are the targeted transport of RNAs to distal sites of synthesis in dendrites and translational control mechanisms to limit synthesis to times of demand. Here we identify dendritic BC1 RNA as a specific repressor of translation. Experimental use of internal ribosome entry mechanisms and sucrose density gradient centrifugation showed that BC1-mediated repression targets translation at the level of initiation. Specifically, BC1 RNA inhibited formation of the 48S preinitiation complex, i.e., recruitment of the small ribosomal subunit to the messenger RNA (mRNA). However, 48S complex formation that is independent of the eukaryotic initiation factor 4 (eIF4) family of initiation factors was found to be refractory to inhibition by BC1 RNA, a result that implicates at least one of these factors in the BC1 repression pathway. Biochemical experiments indicated a specific interaction of BC1 RNA with eIF4A, an RNA unwinding factor, and with poly(A)-binding protein. Both proteins were found enriched in synaptodendritic microdomains. Significantly, BC1-mediated repression was shown to be effective not only in cap-dependent translation initiation but also in eIF4-dependent internal initiation. The results suggest a functional role of BC1 RNA as a mediator of translational control in local protein synthesis in nerve cells.
Wang
Huidong
H
Department of Physiology, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York 11203, USA.
Iacoangeli
Anna
A
Popp
Susanna
S
Muslimov
Ilham A
IA
Imataka
Hiroaki
H
Sonenberg
Nahum
N
Lomakin
Ivan B
IB
Tiedge
Henri
H
D000818:Animals; D001923:Brain Chemistry; D002474:Cell-Free System; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D046911:Macromolecular Substances; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology; D010442:Peptide Chain Initiation, Translational / Q000502:physiology; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020733:RNA, Small Cytoplasmic / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism
C117734:BC1 RNA; D039642:Eukaryotic Initiation Factors; D046911:Macromolecular Substances; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; D020733:RNA, Small Cytoplasmic; D012097:Repressor Proteins; D039601:Eukaryotic Initiation Factor-4A