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Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation.

ABSTRACT: Activity-dependent expression of immediate early genes (IEGs) is critical for long-term synaptic remodeling and memory. It remains unknown how IEGs are maintained for memory despite rapid transcript and protein turnover. To address this conundrum, we monitored Arc, an IEG essential for memory consolidation. Using a knockin mouse where endogenous Arc alleles were fluorescently tagged, we performed real-time imaging of Arc mRNA dynamics in individual neurons in cultures and brain tissue. Unexpectedly, a single burst stimulation was sufficient to induce cycles of transcriptional reactivation in the same neuron. Subsequent transcription cycles required translation, whereby new Arc proteins engaged in autoregulatory positive feedback to reinduce transcription. The ensuing Arc mRNAs preferentially localized at sites marked by previous Arc protein, assembling a "hotspot" of translation, and consolidating "hubs" of dendritic Arc. These cycles of transcription-translation coupling sustain protein expression and provide a mechanism by which a short-lived event may support long-term memory.

SUBMITTER: Das S

PROVIDER: S-EPMC10330212 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation.

Das Sulagna S Lituma Pablo J PJ Castillo Pablo E PE Singer Robert H RH

Neuron 20230425 13

Activity-dependent expression of immediate early genes (IEGs) is critical for long-term synaptic remodeling and memory. It remains unknown how IEGs are maintained for memory despite rapid transcript and protein turnover. To address this conundrum, we monitored Arc, an IEG essential for memory consolidation. Using a knockin mouse where endogenous Arc alleles were fluorescently tagged, we performed real-time imaging of Arc mRNA dynamics in individual neurons in cultures and brain tissue. Unexpecte ...[more]

PMID: 37100055

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Project description:Under conditions of tight coupling between translation and transcription, the ribosome enables synthesis of full-length mRNAs by preventing both formation of intrinsic terminator hairpins and loading of the transcription termination factor Rho. While previous studies have focused on transcription factors, we investigated the role of Escherichia coli elongation factor P (EF-P), an elongation factor required for efficient translation of mRNAs containing consecutive proline codons, in maintaining coupled translation and transcription. In the absence of EF-P, the presence of Rho utilization (rut) sites led to an ~30-fold decrease in translation of polyproline-encoding mRNAs. Coexpression of the Rho inhibitor Psu fully restored translation. EF-P was also shown to inhibit premature termination during synthesis and translation of mRNAs encoding intrinsic terminators. The effects of EF-P loss on expression of polyproline mRNAs were augmented by a substitution in RNA polymerase that accelerates transcription. Analyses of previously reported ribosome profiling and global proteomic data identified several candidate gene clusters where EF-P could act to prevent premature transcription termination. In vivo probing allowed detection of some predicted premature termination products in the absence of EF-P. Our findings support a model in which EF-P maintains coupling of translation and transcription by decreasing ribosome stalling at polyproline motifs. Other regulators that facilitate ribosome translocation through roadblocks to prevent premature transcription termination upon uncoupling remain to be identified. Bacterial mRNA and protein syntheses are often tightly coupled, with ribosomes binding newly synthesized Shine-Dalgarno sequences and then translating nascent mRNAs as they emerge from RNA polymerase. While previous studies have mainly focused on the roles of transcription factors, here we investigated whether translation factors can also play a role in maintaining coupling and preventing premature transcription termination. Using the polyproline synthesis enhancer elongation factor P, we found that rapid translation through potential stalling motifs is required to provide efficient coupling between ribosomes and RNA polymerase. These findings show that translation enhancers can play an important role in gene expression by preventing premature termination of transcription.

Dataset Information

Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation.

Publications

Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation.

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