Translational Control by a Small RNA: Dendritic BC1 RNA Targets the Eukaryotic Initiation Factor 4A Helicase Mechanism

Abstract

Translational repressors, increasing evidence suggests, participate in the regulation of protein synthesis at the synapse, thus providing a basis for the long-term plastic modulation of synaptic strength. Dendritic BC1 RNA is a non-protein-coding RNA that represses translation at the level of initiation. However, the molecular mechanism of BC1 repression has remained unknown. Here we identify the catalytic activity of eukaryotic initiation factor 4A (eIF4A), an ATP-dependent RNA helicase, as a target of BC1-mediated translational control. BC1 RNA specifically blocks the RNA duplex unwinding activity of eIF4A but, at the same time, stimulates its ATPase activity. BC200 RNA, the primate-specific BC1 counterpart, targets eIF4A activity in identical fashion, as a result decoupling ATP hydrolysis from RNA duplex unwinding. In vivo, BC1 RNA represses translation of a reporter mRNA with 5 secondary structure. The eIF4A mechanism places BC RNAs in a central position to modulate protein synthesis in neurons.Local protein synthesis at the synapse, increasing evidence suggests, is one of the key molecular mechanisms that underlie input-specific modulations of synaptic strength and consequently higher brain functions that rely on such synaptic plasticity. Translational control mechanisms in synapto-dendritic domains are thought to be essential for the long-term spatiotemporal modulation of mosaic local protein repertoires. Such mechanisms are therefore attracting increasing interest among neuroscientists and molecular and cellular biologists (reviewed in references 3, 11, 24, 26, 27, 51, 60, and 67).At the same time, there has been growing awareness of the biological significance of small, functional RNAs in eukaryotic cells in general and in neurons in particular (2, 7, 11). Small, non-protein-coding RNAs (npcRNAs) (also known as untranslated RNAs) (9) may be particularly well suited as posttranscriptional regulators of gene expression that enhance brainenvironment interactions (11). Neuronal BC1 RNA is a small dendritic npcRNA (64) that operates as a translational repressor (30,65,66). BC1 RNA, which is targeted to dendrites (38,39) and is abundant at the synapse (13), represses translation at the level of initiation (65, 66).In eukaryotes, translation initiation proceeds in three stages, each of which is mediated by a number of eukaryotic initiation factors (eIFs) (reviewed in references 25 and 43). An eukaryotic initiation factor 2 (eIF2) ⅐ GTP ⅐ GMet-tRNA i ternary complex first binds to the 40S ribosomal subunit to form a 43S preinitiation complex. This complex is subsequently recruited to the mRNA, typically to the 5Ј cap structure, and scans to the initiator codon to form a 48S initiation complex. In the final step, this complex is joined by the large ribosomal subunit to form an 80S monoribosome complex ready for elongation. It is frequently the second step, recruitment of the 43S complex and 48S complex assembly, that is rate limiting and the target for regulation. This step is mediated by the eIF4 family of facto...

From unwinding to clamping — the DEAD box RNA helicase family

“…By contrast, pateamine A stimulates the RNA-stimulated ATPase activity of eIF4A but also seems to be active on eIF4AIII 108 . Similarly to the function of pateamine A, the non-coding RNA BC1 binds specifically to eIF4A and stimulates its ATPase activity but blocks its unwinding activity 109 to prevent translation initiation in neurons.…”

“…Association of programmed cell death 4 (PDCD4) with two molecules of eIF4A (middle) triggers a conformational change that prevents association with eIF4G and thereby inhibits the initiation of translation. Association of eIF4A with the non-coding RNA BC1 inhibits translation by stimulating the ATPase activity of eIF4A (bottom) 109 . eIF4A binding to the small molecules hippuristanol or pateamine A also prevent translation by altering the ATP binding or ATPase activity of eIF4A 105,106 .…”

Knockdown of BC200 RNA expression reduces cell migration and invasion by destabilizing mRNA for calcium-binding protein S100A11

“…Following their expression, BC200 RNAs immediately migrate to dendrites, where they interact and interfere with various translational initiation factors, including eIF4A, eIF4B, and PABP. [1][2][3][4][5][6][7] BC200 RNA is thought to exert local translational control by forming distinctive microdomains in dendrites, and this is believed to contribute to the maintenance of neuronal plasticity. BC1 RNA is the rodent counterpart of BC200 RNA 3 ; the 2 together comprise the BC RNAs.…”

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

“…Plasticity lncRNAs are also implicated in modulating synapse formation and function. In particular, nuclear enriched abundant transcript 2 (NEAT2)/metastasis-associated lung adenocarcinoma transcript 1, brain cytoplasmic RNA 1, and testes-specific Xlinked are all lincRNAs that regulate synaptogenesis, local protein synthesis at the synapse, and fear-conditioning and short-term hippocampal memory consolidation, respectively [40][41][42]. Other lncRNAs are transcribed from genomic loci encompassing protein-coding genes involved in synapse development and functioning.…”